CN106456371B

CN106456371B - Corneal vitrification, methods and devices for producing corneal vitrification, and methods of using the devices

Info

Publication number: CN106456371B
Application number: CN201480072971.5A
Authority: CN
Inventors: O·瑟德阿瑞维克; M·贝里; D·F·赫勒
Original assignee: D FHele; M Beili; O Sedearuiweike
Current assignee: D FHele; M Beili; O Sedearuiweike
Priority date: 2013-11-12
Filing date: 2014-10-13
Publication date: 2020-04-03
Anticipated expiration: 2034-10-13
Also published as: JP2016539688A; US20150230979A1; WO2015073150A1; US9526656B2; US20150230985A1; EP3071161A1; CN106456371A; US20150133901A1; EP3071161A4; US9532904B2; CA2930417A1; CA3011433A1; US9545339B2; CA2930417C; JP6773557B2

Abstract

The invention comprises the following steps: a novel composition of matter (a composite comprising a naturally occurring in vivo cornea in an in situ eye and at least one volume of vitrified non-naturally occurring corneal stromal tissue formed within the naturally occurring corneal stromal tissue), wherein the vitrified tissue changes in structure and properties from its naturally occurring state to a non-naturally occurring glassy state, said changes including but not limited to increased elastic modulus; methods of making and using the novel compositions of matter for altering corneal structure and properties, including but not limited to corneal optical aberrations; wound healing and graft adhesions; and a photovitrification system for producing the new composition of matter, the system including at least one photon source having controllable processing parameters. A reverse template may be added to the corneal vitrification system to enhance vitrification and structural and property changes.

Description

Corneal vitrification, methods and devices for producing corneal vitrification, and methods of using the devices

RELATED APPLICATIONS

Priority OF U.S. provisional application No.61/903,213 entitled "laser apparatus FOR CORNEAL shaping and method OF using the same" (LASER DEVICES FOR CORNEAL SHAPING AND METHODS OF USE THEREOF), filed on 12.11.2013, the entire contents OF which are hereby incorporated by reference in their entirety FOR all purposes.

Technical Field

The present invention relates to vitrifying corneal stromal tissue of an in vivo cornea (in vivo cornea) in an in situ eye (in situ eye). The present invention also relates to methods and devices for producing corneal vitrification, such as photovitrification (photovitrification) methods and devices that use a photon source to produce corneal tissue vitrification; and methods of using the device, such as to alter the corneal structure and corneal properties of an in vivo in situ human cornea, including corneal optical aberrations.

Background

The cornea is a transparent tissue in the front of the eyeball that covers the iris, pupil, and anterior chamber. The cornea is the primary optical element of the eyeball to concentrate light.

Disclosure of Invention

The present invention provides a detailed description of a composition of matter that is a composite of a naturally occurring in vivo cornea of an in situ eye and at least one volume of non-naturally occurring corneal stromal tissue formed within the naturally occurring corneal stromal tissue of the in situ eye in vivo cornea, wherein at least 1% of the at least one volume of non-naturally occurring corneal stromal tissue is vitrified, thereby changing its structure and properties from naturally occurring structures and properties to non-naturally occurring glassy structures and properties. The present invention also provides methods and devices for producing corneal vitrification and using corneal vitrification.

Drawings

FIG. 1 shows a schematic view of a: two-dimensional (2-D) polar coordinates.

FIG. 2: three-dimensional (3-D) cylinder coordinates.

FIG. 3: schematic cross-sectional view of a cornea.

FIG. 4: nonlinear optical microscopy image of the anterior most part of the corneal stroma.

FIG. 5: t required to achieve 0.1% thermal damage (squares) or 1% thermal damage (triangles)_maxAt T_maxIs followed by at T_maxChange in time of (1). The logarithm of time (base 10) is used as the abscissa.

FIG. 6: absorption coefficient of liquid water in the spectral range of 0.70 to 2.50 μm at room temperature.

FIG. 7: absorption spectra of liquid water at 22 ℃ (solid line), 49 ℃ (dotted line) and 70 ℃ (dashed line).

FIG. 8: absorption coefficient of liquid water at 3 temperatures at 1.9 μm wavelength. Linear regression data fits are shown.

FIG. 9: a multi-photon source system for photovitrification.

FIG. 10 shows a schematic view of a: flow chart of the photo-vitrification (PV) process (Tx). Description of the drawings: OFD-eye fixation device (FDS-fiber transmission system).

FIG. 11: eye images with superimposed limbus and pupil edges and centering references (centration reference).

FIGS. 12A to 12D: example of photo-vitrification (Tx) geometry of Tx areas. The concentric circles are spaced one millimeter apart and centered at the pupil center (or other centering reference).

FIG. 13: example of photo-vitrification process geometry of Tx area. The concentric circles are spaced one millimeter apart.

FIGS. 14A (Upper) and 14B (lower): treatment (Tx) of four Tx areas by refractive change (D: diopter) semi-meridian (semimeridian) geometry. The method comprises the following steps: a step function. The following: an S-shaped function.

FIGS. 15A (Upper) and 15B (lower): refractive change (D: diopters) semi-meridians of the treatment (Tx) geometry for the four Tx zones. The method comprises the following steps: tx geometry for reducing regular astigmatism. The following: tx geometry including epithelial thickness difference compensation.

FIG. 16: cross-sectional view of the Heating Affected Zone (HAZ): solid line-HAZ 1, virtualline-HAZ 2. In this figure, note that the radial coordinate is compressed relative to the depth coordinate.

FIG. 17: emsley model eye.

FIGS. 18A and 18B: for three pupil diameters D_mm: 2mm (solid line), 3mm (dashed line) and 4mm (dotted line), the retinal image size X (upper) and possibly UDVA (lower) as a function of defocus.

FIG. 19: temperature profile for matched process conditions with wavelengths of 1.90 μm (triangles) and 1.93 μm (diamonds). The epithelial (Ep) thickness is about 56 μm.

Detailed Description

Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings. Specific embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. In addition, each of the examples, relating to different embodiments of the present invention, are intended to be illustrative, and not restrictive. Any alterations and further modifications of the inventive features illustrated herein, and any additional applications of the principles of the invention as illustrated herein, which would normally occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention.

Throughout the specification, the following terms take the meanings explicitly associated herein, unless the context clearly dictates otherwise. As used herein, the terms "in one embodiment" and "in some embodiments" may, but do not necessarily, refer to the same embodiment. Furthermore, the terms "in another embodiment" and "in some other embodiments" as used herein do not necessarily refer to different embodiments, although they may. Thus, as described below, various embodiments of the present invention may be readily combined without departing from the scope or spirit of the present invention.

In addition, as used herein, the term "or" is an inclusive "or" operator, and is equivalent to the term "and/or," unless the context clearly dictates otherwise. Unless the context clearly dictates otherwise, the term "based on" is not exclusive and allows for being based on additional factors not described. Furthermore, throughout the specification, the meaning of "a", "an" and "the" includes plural references. The meaning of "in" includes "in … …" and "on … …".

The present invention relates to corneal vitrification, as used herein, is understood to result in a novel composition of matter that is a composite comprising an in vivo cornea naturally occurring in an in situ eye and at least one volume of non-naturally occurring corneal stromal tissue formed within the naturally occurring corneal stromal tissue of the in vivo cornea in the in situ eye, wherein at least 1% of the at least one volume of non-naturally occurring corneal stromal tissue is vitrified, thereby changing its structure and properties from naturally occurring structures and properties to non-naturally occurring glassy structures and properties.

Fig. 1 shows a polar coordinate system for describing two spatial coordinates (r, θ) on the anterior surface of the cornea. A given point on the anterior corneal surface may be determined from the radial (r) and angular (θ) coordinates of that point relative to a centering reference (r 0) and an angular reference (θ 0, typically a 3 o' clock angle facing the viewing eye). There is a third spatial (axial) coordinate-depth (z) from the anterior surface of the cornea. FIG. 2 shows a three-dimensional (3-D) cylindrical coordinate system for determining a 3-D point P in a cornea at a depth z from a two-dimensional (2-D) surface point Q. In fig. 2, the depth (axial coordinate) z is shown to increase vertically upwards, but in the subsequent fig. 3, z is shown to increase vertically downwards.

As described herein, the nanostructures, microstructures, and macrostructures and properties of the human cornea, as they exist under in situ conditions, are defined as being in naturally occurring, normal (i.e., non-vitrified) in vivo conditions. Fig. 3 shows a schematic cross-sectional view of a human cornea, on which is shown a representation of structural features, typically organized (organized) in layers at different depths z from the anterior corneal surface (upper part of fig. 3). The central corneal thickness is approximately 550 μm, including (going from the anterior surface to the posterior surface, e.g., from z 0 to z 550 μm):

1-tear film-not shown in fig. 3, about 3 μm thick;

2-epithelium-central thickness of about 56 μm; the epithelium is fixed to the underlying cornea by a basement membrane (also known as the pre-corneal basement membrane); the epithelium has a thickness in a range of, typically 40 to 70 μm, at non-central (r >0) r, θ locations;

3-Bowman's layer (also known as Bowman's membrane or anterior boundary layer) -a non-cellular layer of approximately 15 μm thickness, which is in contact with the epithelial basement membrane; is generally considered to be the acellular portion of the matrix;

4-matrix-central thickness of about 500 μm; is composed of corneal cells; and

5-posterior structures-Descemet membrane, Dua layer (not shown), and endothelium.

For the purposes of the present invention, Bowman's layer is considered to be the acellular portion of the anterior matrix.

For the purposes of this disclosure, corneal tissue or components thereof specifically intended to be substantially (materialally) affected by the treatment described herein is designated as the disclosure "target" of the invention, while other (non-target) corneal tissue or components thereof are not intended to be substantially affected by the treatment described herein, and are therefore regions intended to minimize deleterious effects. Corneal stromal tissue, including Bowman's layer, is a target (target) of the present invention. The stromal thickness at the central cornea is about 500 μm, and the stromal thickness at the peripheral cornea increases to a value of about 600 μm or more. In some embodiments, the anterior region of the corneal stroma (e.g., the anterior one-third or about the anterior 150 to 200 μm thickness) that includes the Bowman's layer is the target region. In some embodiments, the anterior stroma from which the Bowman's layer is removed is the target region. This anterior stromal region comprises a "sutured" collagen sheet, which has an anisotropic structure and biomechanical properties typically associated therewith. FIG. 4 shows the microstructure of the Bowman's layer (above) and the matrix to a depth of about 160 μm; the epithelium is not shown in the figure. Unlike posterior matrices composed of collagen fibrils and collagen lamellae that form regular layers aligned parallel to the anterior corneal surface with low interlaminar adhesion, the most anterior portion of the matrix is composed of randomly arranged fibrils and lamellae that are highly interconnected and have branches spanning multiple layers, providing much greater interlaminar adhesion and modulus. Many of the anterior fibrils are transverse (also known as oblique), even forming "sutures" (sutures) into Bowman's layer. In some embodiments, the goal of this anterior stromal tissue is to maximize the beneficial treatment effects on all corneal structures, and minimize the deleterious effects on all corneal structures.

The stroma is the main structural part of the cornea, which defines the shape of the cornea. Under naturally occurring in vivo conditions, the matrix is a fiber/substrate composite with unique optical properties. The matrix has high light transmission with little or no light scattering. The matrix also has unique anisotropic biomechanical properties that are a function of temperature and time during which the matrix is subjected to a particular temperature, as described in detail below. Corneal cells are the predominant cells within the stroma, accounting for as much as 10% of the stroma' dry weight. The major fibrous component in the matrix fiber/substrate composite is type I collagen. Type I collagen is highly organized in fibrils and lamellae of the corneal stroma in vivo at normal physiological temperatures. In addition to cells, the components in the matrix fiber/substrate complex are called extracellular matrix (ECM); in addition to the collagen fiber nanostructure components, the ECM includes Proteoglycans (PGs), glycosaminoglycans (GAGs), water, inorganic ions, and other nanostructure components. Under naturally occurring conditions, water constitutes more than 75% by weight of the corneal stroma in vivo.

In its naturally occurring condition, the cornea in situ in the eye has a lenticular structure that focuses light into the eyeball. Additional focusing is provided by the lens of the eyeball in order to form an image on the light-sensitive portion of the retina of the eyeball. The retina has structures important for central vision (the macula and the fovea within the macula). In many cases, optical aberrations of the cornea and/or lens result in the inability to accurately focus images on the retina. In some cases, another cause of inaccurate focusing is an inaccurate axial length of the eyeball that does not match the focusing power of the cornea plus the crystalline lens. In some embodiments, the correction of corneal optical aberrations by the present invention can be used to accurately form a focused image on the retina. In some cases, ocular diseases that cause central visual field defects and scotomas, including but not limited to retinal diseases (such as age-related macular degeneration), reduce vision as the image is focused onto the dysfunctional portion of the macula. In some embodiments, the correction of corneal optical aberrations by the present invention can be used to magnify and/or reposition images in order to use functional portions of the retina.

In some cases, in situ intra-ocular corneal keratomes have a naturally occurring and/or iatrogenic ectasic disorder, such as keratoconus or corneal ectasia after corneal resection, which is progressive in nature. In some embodiments, the increase in corneal elastic modulus of the present invention can be used to slow the progression of these diseases. In some embodiments, the present invention's correction of corneal optical aberrations can also be used to improve vision in the dilated condition.

The term "corneal vitrification" as used in connection with the present invention described herein is understood to refer to the type of vitrification that occurs in the in vivo cornea of an in situ eye, involving the generation of a novel composition of matter that is a composite comprising a naturally occurring in vivo cornea of an in situ eye and at least one volume of non-naturally occurring corneal stromal tissue formed within the naturally occurring corneal stromal tissue of the in situ eye cornea, wherein at least 1% of the at least one volume of non-naturally occurring corneal stromal tissue is vitrified, thereby altering its structure and properties, from naturally occurring to non-naturally occurring glassy structures and properties. The term "corneal photovitrification" (PV) used in connection with the invention described herein is understood to mean corneal vitrification produced by photons in the cornea in vivo of an eye in situ. As an example, the mechanical properties of vitrified stromal tissue are altered relative to those of naturally occurring stromal tissue. As an example, the elastic modulus of the vitrified stromal tissue is increased relative to the elastic modulus of a naturally occurring non-vitrified cornea. As an example, the increase in the elastic modulus of the vitrified stromal tissue includes at least one of: an increase in axial modulus of 10% (wherein the axial modulus traverses the cornea from anterior to posterior stroma), an increase in shear modulus of at least 10%, or any combination thereof. The present invention includes at least three types of corneal photovitrification, or any combination thereof, which can be distinguished as:

photochemical (where a photochemical reaction causes vitrification), optomechanical (where photons produce a mechanical effect that causes vitrification), and photophysical (where photons produce a physical effect that includes heating that causes vitrification).

In some embodiments, two or more types of PV may occur, such as a combination of photochemical and photophysical processes. In some embodiments, photophysical PV may include the use of photon absorption modulators including dyes, nanorods, or any combination thereof. In some embodiments, it should be understood that the term "light" also encompasses any form of electromagnetic energy (i.e., photons), including, but not limited to, photons having wavelengths across the Ultraviolet (UV), Visible (VIS), Near Infrared (NIR), Infrared (IR), Microwave (MW), and Radio Frequency (RF) regions of the electromagnetic spectrum ranging from about 300 nanometers to 1 meter. In some embodiments, photons can be used at sufficient intensity to cause multiphoton (e.g., simultaneous two-photon) absorption that alters the in vivo corneal stromal tissue of the in vivo cornea in an in situ human eye, thereby producing corneal stromal alterations, including vitrification with the goal of improving favorable alteration.

In some embodiments, corneal tissue modification is provided by using a non-optical energy source including, but not limited to, an acoustic energy source that generates ultrasound waves having a frequency in the range of about 20 kilohertz to 200 megahertz; in this case, the acoustic energy produces acoustic vitrification.

In some embodiments, the methods of corneal vitrification include applying an external stress to an anterior surface of a cornea during a corneal vitrification process to improve structural and property changes in a vitrified volume of stromal tissue. The addition of the external stress applied to the anterior surface of the cornea is related to the pressure applied to the at least one treated volume of the in vivo corneal stromal tissue of the in situ cornea in the eye to improve the alteration of the structure and properties of the vitrified stromal tissue. As one example, the external stress densifies an in vivo corneal stroma of the in situ eye in vivo cornea, wherein the external stress is associated with at least a 5% increase in a density of the corneal stroma in at least one treated volume of in situ eye in vivo corneal vitrifying stromal tissue of the in vivo cornea.

In some embodiments, heating the corneal stromal tissue causes a change in the structure and properties of the tissue, including but not limited to: vitrification, modulus of elasticity, or any combination thereof. As used herein, at least one Photovitrification (PV) heating affected zone ("HAZ") is the volume of tissue affected by PV treatment (Tx) in the PV Tx zone; the PVTx region is defined as the foremost surface of the PV HAZ, which extends axially into the tissue to a maximum depth z_max. The geometric volume of the PV HAZ is typically defined in 3-D cylindrical coordinates r, θ, z-see fig. 2.

In some embodiments, corneal vitrification in the PV HAZ is produced, at least in part, by a "moderate temperature rapid heating" method-see below.

Corneal stromal tissue vitrification according to the present system may include alterations to corneal stromal tissue in vivo, including but not limited to:

a-changes in matrix nanostructures, microstructures, and macrostructures, including but not limited to fiber/substrate composites;

b-alterations in matrix fiber/substrate and cellular function, including but not limited to metabolism, motility, and interactions including signaling at all scales;

c-changes in matrix organization properties including, but not limited to, mechanical, optical, thermal and transport properties on all scales;

d-or any combination thereof.

For example, in some embodiments, the following changes to corneal stromal tissue in vivo are at moderate temperatures (e.g., a maximum temperature T of up to about 100℃.) in accordance with the systems of the present invention_max) Rapid heating (e.g., with a heating history that includes heating to T in less than about 1 second_maxAnd is maintained at T before cooling_max) The following occurs:

an increase in the elastic modulus of the corneal stromal tissue in the treated volume;

wherein the treated volume is comprised at a maximum temperature T_maxTo a lower temperature T_max-corneal stromal tissue treated in a temperature range of 5 ℃; wherein the increase in the elastic modulus of the vitrified matrix tissue may comprise at least one of: an increase in axial modulus of 10% (wherein the axial modulus extends through the cornea from anterior to posterior stroma), an increase in shear modulus of at least 10%, or any combination thereof.

In some embodiments, the corneal stromal alteration comprises vitrifying at least 1% of at least one treated volume element within at least one HAZ; the treated volume is already at the maximum temperature T_maxTo a lower temperature T_maxIs treated in a temperature range of-5 ℃.

In some embodiments, advantageous changes, including but not limited to those described above, are maximized (with respect to considerations including but not limited to targeting, safety, effectiveness, and predictability), and additionally, deleterious effects, including but not limited to deleterious changes to the structure, function, and properties of the non-vitrified and vitrified matrix volumes are minimized.

In some embodiments, the maximum temperature T for altering tissue within a Heating Affected Zone (HAZ)_maxThe range includes, but is not limited to, T between 50 ℃ and 100 ℃ for a thermal history range between 20 milliseconds (ms) and 2000ms_max. In some embodiments, the range of change in the treated in vivo corneal stromal tissue in the HAZ includes, but is not limited to, 1% to 50% vitrification of the treated volume, and a 10% to 10% increase in corneal elastic modulus00% with at least one of the following conditions: an increase in axial modulus of 10% to 1000% (wherein the axial modulus extends through the cornea from anterior to posterior stroma), an increase in shear modulus of at least 10% to 1000%, or any combination thereof, wherein the treated volume is included at the maximum temperature T_maxTo a lower temperature T_max-tissue treated in a temperature range of-5 ℃.

The reaction rate for the rate process has a rate coefficient k that varies with temperature_i(T), where a typical Arrhenius (Arrhenius) equation for each rate process i is:

k_i(T)＝A_iexp(-E_a,i/RT)

wherein k is_i(T) is the temperature T [ units: k]Rate coefficients of [ unit: s^-1]，

A_iRefers to the pre-exponential factor [ unit: s^-1]，

E_a,iIs activation energy [ unit: j/mole]And an

R is the gas constant [ ═ 8.314J/(kmol) ].

Examples of rate processes are: epithelial lesions (i ═ 1) and stromal alterations (i ═ 2); i-1 and 2 may be a total rate process comprising a number of individual processes; the "rate control step" may control the overall rate. These rate processes have a small rate coefficient k at low T_i(T) its "threshold" is equal to the activation energy E_a,iWhereas the rate coefficient increases exponentially with increasing T, which results in exponential amplification of the temperature difference effect. All corneal stromal thermal rate processes relevant to the present invention (including but not limited to thermal injury and thermochemical processes) have a total rate coefficient that can be expressed in the form of the arrhenius equation.

Each rate process of corneal vitrification is a kinetic process; the extent to which each process occurs depends on its thermal history (i.e., specific temperature versus processing time). Each process does not reach T when heated_maxOccurs immediately but is controlled by the arrhenius rate coefficient of the process. Extent of this process (of component A to component B, component B to component C, etc.) "Percent conversion ") is different under fast heat/short heat duration conditions where the cornea is heated rapidly to each T, compared to slow heat/long heat duration conditions_maxThen at T_maxThe next incubation is continued for a short period of time (e.g., over a 1 second period). Generally, the faster the heating (and the shorter the total duration of the heating), T_maxThe higher must be to produce the same percent conversion. FIG. 5 shows the required T_maxExample values to achieve 0.1% and 1% conversion in heating durations between 100 milliseconds and 10 seconds; the arrhenius parameters in these examples were chosen to be: a is 3.0 × 10⁴⁴Second of^-1,E_a293 kJ/mole. The parameters in these examples are thermal injury parameters for non-stromal cell necrosis. (the acellular thermal injury parameter is dependent on the acellular corneal injury process, which occurs mainly at higher temperatures for the same heating time as compared to cellular necrosis.) As an example, if at T_maxThe duration of the rapid heating is 1 second, and assuming 0.1% thermal damage is acceptable, then T_maxMay be 49.2 deg.C, and T, assuming 1% thermal damage is acceptable_maxMay be 56.2 deg.c higher (and, if 10% of thermal damage is acceptable, T may be_maxIs 63.4 c-not shown in fig. 5). In addition, the value of the process conversion percentage in fig. 5 is a strict upper limit value because only the center of the Heating Affected Zone (HAZ) having a small volume in the r, θ, z coordinate system is heated to T_max(ii) a Other parts of the HAZ are heated to below T_maxThe temperature of (2). Since the rate process occurs with a rate coefficient that increases exponentially with increasing T, the treatment is primarily on the volume (V) being treated_Tx) In T_maxOr with T_maxThe difference does not exceed a few degrees. In the present invention, V_TxIs defined as being at T_maxTo T_max-a volume to be treated at a temperature between 5 ℃. In some embodiments, the system of the present invention comprises a result, wherein the result may be a corneal change, wherein the cornea changesThe change may be corneal vitrification, wherein the corneal vitrification energy is maximized, and wherein deleterious effects including, but not limited to, thermal damage can be minimized. In some embodiments, the arrhenius parameters in the process may be determined, as well as direct measurements of the targeted beneficial and undesirable detrimental effects.

In some embodiments, the range of thermal damage (i.e., heat-induced cell necrosis) to each in vivo corneal structure (including but not limited to the corneal epithelial basement) within each treated volume is defined as between 1% and 50% thermal damage. In some embodiments, the maximum temperature T generated within the corneal epithelial basement and the anterior basement membrane_maxIncluding but not limited to a T between 40 deg.C and 75 deg.C for a thermal history range between 20 milliseconds (ms) and 2000ms_max. In all cases, T_maxDepending on the duration of heating.

In some embodiments, a system for vitrifying at least one treated volume of corneal stromal tissue of a human cornea in situ in an eye is used to alter corneal structure and corneal properties, including but not limited to altering corneal elastic modulus and corneal optical aberrations, and including but not limited to altering adhesions of apposed (aposed) stromal tissue after healing of a corneal wound; adhesion of donor-transplanted corneal stromal tissue or synthetic graft material to apposed recipient donor stromal tissue, or any combination thereof. In some embodiments, a system for vitrifying at least one treated volume of corneal stromal tissue of a human cornea in situ in an eye is based on at least one photon source configured to generate at least one photon output comprising at least one photon wavelength corresponding to 20 to 300cm at room temperature (T; about 20 ℃) in the range of 20 to 300cm^-1Absorption coefficient of liquid Water in the range (α). figure 6 shows the absorption spectrum of liquid water at room temperature T in the 0.7 to 2.5 μm spectral region (i.e., absorption coefficient α vs. photon wavelength. the absorption coefficient in figure 6 is given in three separate logarithmic scales for the three wavelength regions; between about 1.41 to 1.49 μm, between about 1.86 to 2.14 μm, and between about 1.86 to 2.14 μm20 to 300cm can be obtained at long wavelengths between 2.28 and 2.50 μm and at wavelengths longer than 2.50 μm (not shown in FIG. 6)^-1α of water in between, fig. 7 shows absorption spectra of liquid water at room temperature (22 ℃) and at two elevated temperatures (49 ℃ and 70 ℃), α of water increases with increasing T and α decreases with increasing T at wavelengths greater than about 1.93 μm, as an example, fig. 8 shows temperature dependence of water at 1.90 μm at α of T, where α of T is measured in fig. 7 and shows a measurement of a linear fit of α to T, fig. 8 shows, in some embodiments of the invention, at least one photon output comprising at least one photon wavelength between about 1.86 to 1.93 μm is used to change corneal structure and corneal properties, including but not limited to changing corneal elastic modulus and corneal optical aberration, or including but not limited to changing adhesion of juxtaposed tissue after a corneal wound, a transplanted corneal tissue or synthetic graft material to a donor stroma tissue, or a donor tissue graft tissue, or a donor tissue graft tissue, including but not limited to changing adhesions, or a synthetic tissue graft tissue, including but not limited to increasing tissue adhesions, using at least one photon output comprising at least one photon output in a combination of a donor tissue, including but not limited to changing adhesions, and increasing tissue adhesion, including but not limited to a tissue, and increasing tissue, including but not limited to increasing tissue, and increasing tissue adhesion, including at least one of a donor tissue, including but not limited to a tissue, including but to a tissue, including a tissue graft.

It should be noted that water is the predominant chromophore used for tissue absorption throughout the 0.7 to 2.5 μm spectral region shown in FIG. 6, so the present invention uses corneal absorption coefficients in this region based at least in part on the water content in the cornea. at wavelengths greater than 2.5 μm in the mid-infrared spectral region, non-water components of the cornea typically have substantial absorption_CorneaApproximately given by:

α_cornea＝α_{Water (W)}mf_{Water (W)}ρ_Cornea/ρ_{Water (W)}Equation 1

Wherein, α_{Water (W)}Is the absorption coefficient of the liquid water and,

mf_{water (W)}Is the mass fraction of water in the cornea,

ρ_corneaIs the density of the cornea, an

ρ_{Water (W)}Is the density of water (0.9978 at T ═ 20 ℃).

Mass fraction mf of water in cornea_{Water (W)}Depending on the hydration of the cornea (which generally varies from anterior to posterior, from surface to interior, daytime, etc.), but is about 0.75 for the anterior stroma and about 0.79 for the posterior stroma. Generally, the density ρ of the cornea_CorneaGreater than about 5% of the density of water. In some embodiments, the density ratio ρ is assumed_Cornea/ρ_{Water (W)}With the temperature remaining constant in the range of T-20 ℃ to 80 ℃, the present invention employs the following approximate equation (2):

α_{cornea, T}About 0.8 α_{Water, T}Equation 2

In the 1.8 to 2.2 μm spectral region shown in fig. 7, the corneal room temperature T (about 20 ℃) absorption spectral shape is the same as that of water in some embodiments, the α value of the cornea in the range of T ═ 20 ℃ to 80 ℃ is about 80% of the α value of water in the 1.8 to 2.2 μm spectral region.

In some embodiments, the range of room temperature (T; about 20 ℃) water absorption coefficient (α) includes, but is not limited to, 20 to 300cm^-1α in some embodiments, the range of photon wavelengths includes a water absorption coefficient at that wavelength of 20 to 300cm^-1A wavelength in the range between.

In some embodiments, the corneal vitrification methods and devices thereof employed in the present invention can be used to alter structures and properties, including but not limited to, corneal elastic modulus and corneal optical aberrations of an in vivo human cornea in an in situ eye, including at least one treated volume of vitrification of an in vivo corneal stromal tissue formed in a naturally occurring corneal stromal tissue of the in vivo cornea in the in situ eye. In some embodiments, vitrification within the treated stromal tissue volume increases the magnitude and duration of changes in corneal structure and corneal properties (including, but not limited to, corneal elastic modulus and corneal optical aberrations).

In some embodiments, the invention employs methods and apparatus thereof that generate photons to alter corneal stromal tissue in vivo,

wherein the treated volume is comprised at a maximum temperature T_maxTo a lower temperature T_maxCorneal stromal tissue treated in a temperature range between-5 ℃.

In some embodiments, the areas of Photovitrification (PV) heating influence (HAZs) are produced by rapidly heating the in vivo corneal stromal tissue of the in vivo cornea in an in situ human eye during 100 milliseconds of laser irradiation producing a peak temperature increase of about 50 ℃ during such laser irradiation, which corresponds to a heating rate of about 500 degrees (c) per second. In some embodiments, similar HAZs are generated in situ in vivo corneal stromal tissue of an in vivo cornea of a human eye by rapid heating in the HAZs using an energy source that produces a heating rate of between 5 ℃/s and 20000 ℃/s for a sustained period of time, typically one or more heats, each for a time period of between 20 and 2000 milliseconds,this provides the required thermal history to enhance vitrification of the treated corneal stromal tissue and minimize deleterious effects including, but not limited to, thermal injury (i.e., non-stromal cell necrosis caused by heating). Since the effects of heating on the corneal stroma and other corneal structures are all formed by dynamic phenomena, typically with a rate coefficient that can be expressed by the arrhenius equation (as described above), not only is the maximum degree of heating (to the maximum temperature T) controlled in order to achieve the targeted beneficial heating effects (including vitrification) but also to minimize the undesirable detrimental effects as much as possible_max) Is necessary and it is also necessary to control the thermal history. The optimal thermal history is herein denoted by the term "medium temperature rapid heating".

In some embodiments, the present invention produces a moderate temperature rapid heating effect that maximizes the beneficial in vivo corneal stromal changes, including vitrification, and minimizes deleterious effects by judicious selection of the highest (but moderate) temperature and rapid heating rate. T can be selected by_maxAnd at T_maxThe combination of duration of lower heating, which is to define the upper limit of the amount of detrimental effect (including percent thermal damage), and to redefine the thermal history of heating, including T_maxAnd at T_maxThe lower heating duration is combined to produce a detrimental effect of not more than the upper limit. For example, FIG. 5 may be used to select moderate temperature rapid heating conditions that limit thermal damage to 0.1% or 1% of the volume of the HAZ.

In some embodiments, the invention relates to a device for irradiating in vivo corneal stromal tissue of an in vivo cornea of an in situ human eye with photons to produce vitrification that remains in a durable vitrified state at physiological temperatures after the vitrification process has been completed. In some embodiments, the PV device is configured to exhibit radiation characteristics such as, but not limited to, wavelength, irradiance, and their spatial and time-dependent distributions, so as to provide targeted enhancement of beneficial changes in the anterior stroma and a minimal degree of enhancement of deleterious effects on the corneal structure. In some embodiments, the PV device is a non-laser device configured to exhibit Intense Pulsed Light (IPL) radiation characteristics such as, but not limited to, wavelength distribution, optical irradiance, and their spatial and time-dependent distributions.

In some embodiments, as described in detail herein, the PV devices of the present invention are used in conjunction with an auxiliary device that applies external stress to the anterior surface of the cornea during the corneal vitrification process. An auxiliary device, a reverse template (retrovertemplate impression) applies pressure into at least one vitrified treated volume of in vivo corneal stromal tissue of in vivo cornea in an in situ eye. The reverse template also densifies the vitrified treated volume of stromal tissue of the in vivo cornea in the in situ eye by an external stress, wherein the external stress is associated with at least a 5% increase in stromal density within at least one treated volume of the in vivo corneal vitrified stromal tissue of the in situ cornea in the in situ eye. The inverse template provides external stress to the vitrified treated volume of the cornea to enhance targeted beneficial effects while minimizing deleterious effects (including, but not limited to, e.g., thermal damage).

In some embodiments, the heating duration ranges from, but is not limited to, between 20 to 2000 milliseconds of heating duration. In some embodiments, the range of heating rates includes, but is not limited to, heating rates between 5 ℃ per second and 20000 ℃ per second.

In some embodiments, a system for photovitrifying corneal stromal tissue (PV) of at least one treated volume of corneal stromal tissue is used for alteration of corneal structure and corneal properties, including but not limited to corneal modulus and corneal optical aberrations, or for adhesion of apposed stromal tissue after healing of a corneal wound; adhesion of donor-transplanted corneal stromal tissue or synthetic graft material to juxtaposed recipient donor stromal tissue, or any combination thereof for use in an in situ in vivo human cornea in an eye; the system includes several elements including: a-at least one photon source, a B-fiber transmission subsystem, and a C-eye fixation device. The details of this element are as follows:

a-at least one photon source configured to generate at least one photon output comprising at least one photon wavelengthCorresponding to 20 to 300cm at room temperature (about 20 ℃ C.)^-1Liquid water absorption coefficient within the range. The at least one photonic output is also configured to include a single photonic pulse, a sequence of photonic pulses, or any combination thereof, wherein each pulse has a predetermined time-dependent waveform containing a pulse energy within a time window of 20 to 2000 milliseconds, wherein the plurality of pulses are separated by time periods of 10 to 200 milliseconds.

A B-fiber transmission subsystem comprising:

at least one optical fiber configured to generate a predetermined photonic output energy within each processing region,

optics and/or a divider associated with a distal end of the at least one optical fiber for generating a predetermined photon output energy within each processing region,

a specially shaped and/or combined distal end of the at least one optical fiber, such specially shaped distal end comprising a non-circular cross-section (including elliptical and stadium shaped) and flat distal end surface, a distal end comprising a circular cross-section and curved distal end surface, and such combined distal ends as follows: the distal end having a flat distal end surface, the combined distal end comprising a combined tip having a partially circular cross-section and at least one flat side combined on their flat sides, or any combination thereof,

wherein the photon output is capable of 20 to 1000 millijoules (mJ) per pulse per treatment area [ at least one wavelength at which the water absorption coefficient at room temperature (about 20 ℃) is 20 to 300cm^-1Within the range of]Within the range of (1);

wherein the fiber optic transmission subsystem is configured to transmit the at least one predetermined photonic output energy to the eye fixation device; wherein the fiber optic transmission subsystem is configured to transmit the at least one predetermined photon output energy to an optical element forming part of the posterior structure of the eye fixation device, the optical element being comprised of a thermally conductive optical material in contact with the anterior corneal surface, the predetermined photon output energy being transmitted through the anterior corneal surfaceThe optical element is transferred to at least one treatment zone on the cornea, the treatment zone being between 0.2 and 100mm²Within the range of (1); wherein the shape of each processing region has a shape selected from the group consisting of: circular, overlapping circular, elliptical, oval, stadium, polygonal with rounded corners, arc, circular, or any combination thereof; wherein one or more treatment zones are organized about the pupil center (or other centered reference, such as a coaxially observed corneal light reflection point) in a treatment (Tx) geometric arrangement, wherein the shape of the Tx geometric arrangement is selected from the group consisting of:

i) an axisymmetric geometric arrangement comprising a set of even-numbered multiples (2,4,6,8,10, or 12) of the processing region;

ii) an asymmetric geometric arrangement comprising a set of odd multiples (1,3 or 5) of the treatment area; or

iii) any combination thereof;

wherein each circular treatment zone is centered at a predetermined polar coordinate (r, θ);

wherein the non-circular treatment area has a geometric reference selected from the group consisting of:

the center, axis, pole, arc length and width, or annular width of the overlapping circles, the geometric reference being at a predetermined polar coordinate (r, θ);

wherein the fiber optic transmission subsystem is configured to produce a smooth (see below), low magnitude corneal curvature gradient between and within at least one of: an angle segment, a radius segment, or any combination thereof;

wherein the corneal curvature gradient is between 0.1 and 3 diopters (D)/mm;

wherein the fiber optic transmission subsystem is configured to be mounted on the eye fixation device;

c-an eye-fixation device for the eye,

wherein the eye fixation device is configured to deliver the at least one predetermined photon output energy to at least one treatment region on a human cornea in vivo in an in situ eye,

wherein, this eye fixing device includes:

suction ring assembly and

an optical element in contact with the anterior surface of the cornea,

wherein the optical element is comprised of a thermally conductive optical material, the optical material being sufficiently designed to:

is substantially transmissive to the at least one photon output,

the surface of the optical element that contacts the anterior surface of the cornea is flat, an

Has sufficient thermal conductivity and sufficient dimensions to provide a temperature within 5 degrees from the physiological corneal surface T (approximately 35 ℃) during the photovitrification process. In some embodiments, the optical element in contact with the anterior corneal surface may be comprised of, but is not limited to, the following: sapphire (chemical composition: Al)₂O₃) Infrared silicon (infra) quartz (a substantially transparent low-OH quartz), diamond, or any combination thereof. In some embodiments, the optical element in contact with the anterior corneal surface can have a high optical quality such that photons are transmitted through the optical element without undergoing substantial scattering. In some embodiments, at least a portion of the optical elements of the eye fixation device comprise: a proximal surface (not in contact with the cornea), an optical element body, a distal surface (in contact with an anterior surface of the cornea), or any combination thereof, at least a portion of the optical element of the ocular fixation device providing substantial photon scattering to: expanding the photon spatial distribution to increase the treated (Tx) area, diffusing the photon spatial distribution to make the light irradiation "uniform" over the Tx area, or any combination thereof.

In some embodiments, the fiber optic transmission subsystem can be configured to be separate from the eye fixation device, and the secondary optical element and eye tracking system can be used to locate the photon output at the location of the treatment (Tx) region on the cornea.

In some embodiments, the eye fixation device can be configured with a plano-concave optical element mounted on the cornea using a suction ring assembly, wherein a concave surface of the optical element is in contact with an anterior surface of the cornea.

In some embodiments, a system for altering corneal structures and properties, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination thereof, of a human cornea in an in situ eye, is configured to fail to avoid a corneal wound healing response, but to initially substantially reduce deleterious corneal wound healing effects.

In some embodiments, a system for altering corneal structures and properties, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination thereof, of an in vivo human cornea in an in situ eye, configured to generate a predetermined single photon output energy that is used to irradiate each treatment region on a corneal surface so as to produce a spatial thermal history that causes a predetermined corneal stroma change that results in improved vision; and wherein the system for altering corneal optical aberrations, for altering corneal structure and properties, or any combination thereof, of the human cornea in situ in the eye is configured to form a predetermined treatment region, shape and geometric arrangement selected to affect at least one of the following parameters: at least one lower order optical aberration, at least one higher order optical aberration, at least one optical aberration that cannot be predominantly (at least 51%) described by Zernike (Zernike) polynomials (and coefficients) up to and including the 8 th radial order, or any combination thereof. In some embodiments, the optical aberration may include a corneal optical aberration, a lens optical aberration, or any combination thereof.

In some embodiments, the at least one photon source is a semiconductor diode laser that produces at least one photon output. In some embodiments, the at least one photon source is a solid state laser doped with at least one ion that produces at least one photon output. In some embodiments, the at least one photon source is a strong pulsed light source comprising a flash lamp and associated electrical energy storage and release electrons. In some embodiments, the at least one photon source is equipped with wavelength selective and bandwidth narrowing optical elements that provide photon output. In some embodiments, wavelength selection and bandwidth narrowing is provided by at least one of the following elements, namely: an optical transmission filter, an optical reflection filter, an optical diffraction filter, a volume bragg grating, a birefringence filter, a diffraction grating, a prism, or any combination thereof.

In some embodiments, the plurality of semiconductor diode laser photon outputs are oriented such that each photon output is directly coupled into a single fiber of the fiber transmission subsystem, wherein each of the plurality of photon outputs is individually controlled in terms of at least one output characteristic selected from the group consisting of: wavelength, output shape, time-dependent pulse distribution per pulse (i.e., pulse shape), time-dependent pulse sequence in the case of multiple pulses, and energy per pulse.

In some embodiments, at least one of the photon outputs is a collimated or concentrated beam of photons, the beam being configured to be directed such that each beam:

i) directly into the individual fibers of the fiber optic transmission subsystem,

ii) split into two or more beamlets by an optical subsystem comprising at least one mirror, at least one beam splitter, at least one focusing lens, at least one dimmer, or any combination thereof, wherein each of the beamlets is coupled into a single fiber in a fiber optic transmission subsystem, or

iii) any combination thereof,

wherein each photon output (beam and/or beamlet) is individually controlled in terms of at least one of the following output characteristics selected from the group consisting of: a wavelength, an output shape, a time-dependent pulse profile (i.e., a pulse waveform) of each pulse, a time-dependent pulse sequence in the case of a plurality of pulses, and an energy of each pulse, wherein the at least one dimmer is configured to adjust at least one characteristic of each photonic output (beam and/or beamlet); and wherein the at least one dimmer is selected from the group consisting of: an iris, a variable speed drive filter, a shutter, or any combination thereof.

In some embodiments, the time-dependent pulse sequence is configured to stabilize changes in corneal structure and properties, including but not limited to corneal elastic modulus, corneal optical aberrations, corneal wound healing, adhesion of transplanted tissue, or any combination thereof, of a vitrified in situ in-eye cornea comprising at least one treated volume of corneal stromal tissue, the stabilization comprising heating at a lower temperature than the temperature of the initially treated tissue. As an example, in some embodiments, at least one pulse can heat at least one treated volume to T_maxAnd for a short heating time, and then at least one of the following pulses (or the continuation of the first pulse at a lower irradiance) is capable of heating the at least one treated volume to below T_maxAnd for a heating time longer than the first pulse. In some embodiments, the adhesivity of a corneal tissue attachment moiety (including but not limited to the transplantation of a donor corneal disc to a recipient cornea) can be enhanced by vitrification and stabilization of the juxtaposed corneal stromal tissue. Notably, the vitrification and stabilization process described herein is significantly different from micro-welding, which has previously been used to improve adhesion by "melting" collagen (including denaturation). The present invention relates to "medium temperature rapid heating" which does not cause collagen melting.

In some embodiments, the fiber optic transmission subsystem includes at least one of the following elements: one or more optical fibers, separating elements, optical elements, mechano-electronic actuators, or any combination thereof, configured to change a treatment area and treatment geometry on an in vivo cornea of an in situ eye by changing a separation of a distal end of the optical fiber, a lens, a mirror, a prism, or any combination thereof, relative to an anterior surface of the cornea. In some embodiments, the lens is at least one of the following: a spherical lens, a cylindrical lens, a Powell or other aspheric lens, a diffractive lens, a axicon lens, a microlens, or any combination thereof. In some embodiments, the mirror is at least one of: a flat mirror, a concave mirror, an aspherical mirror, or any combination thereof. In some embodiments, the prism is a Dove (Dove) prism.

In some embodiments, the at least one photon source is configured to alter an in vivo cornea of the eye in situ using the optical scanner. The photon source is configured to have suitable radiation characteristics (including wavelength, time-dependent energy output, etc.) and has an output beam that is focused by a long focal length lens and directed to a galvanometer-mounted scanning mirror configured to scan the beam over an array of optical fibers. In some embodiments, the components of the inventive device with optical scanner include some of the following:

1-lens, creating a small diameter (about 100 to 200 μm) focused spot on an optical fiber (typically 500 μm inner diameter) located in an optical fiber array,

2-mirrors, highly reflective at the photon wavelength,

3-galvanometer, with fast positioning speed (less than about 1ms from fiber to fiber in a fiber array),

4-fiber array, containing 1 to 16 fibers,

5-scan control electronics for driving galvanometers, and/or

6-computer module programmed to generate a step-and-hold sequence of predetermined beam positions.

In some embodiments, examples of galvanometer assemblies that may be used in the apparatus of the present invention include:

an A-ray scanner comprising a single axis galvanometer and position detector (both from Cambridge Technology,125Middlesex Turnpike, Bedford, MA 01730), such as model 6210H, and a 3mm aperture mirror mounted on the galvanometer motor, and

B-Single-axis servo drive (e.g., model 671, which interfaces with computer control).

In one embodiment, the optical scanner may be programmed to step-and-hold a sequence that delivers a predetermined irradiance of the optical fibers in the optical fiber array. For example, for 8 fibers in a linear array, fibers 1-8 may each receive 100ms of irradiation in a linear sequence or a sequence designed to "homogenize" the effects of treatment (Tx) within an octagonal ring of 8 Tx regions in each ring (such as 1-4-7-2-5-8-3-6). In another embodiment, multiple irradiations of each fiber can be used for further homogenization; for example, a 1-4-7-2-5-8-3-6 sequence may be used for 10ms of irradiation, followed by each of a plurality of repeating sequences for 10ms of irradiation, or some other sequence for 10ms of irradiation. In some embodiments, the purpose of "homogenization" is to achieve equal Tx effect within each Tx zone, thereby avoiding causing astigmatism.

In some embodiments, the invention also includes an aid to centering, out-of-plane orientation (i.e., tilt), and goniometry for simple and accurate alignment of the ocular fixation device with respect to the center and angular reference, as well as for reducing parallax caused by tilt. In some embodiments, a reticle with crosshairs and angle markings is used to assist in centering and goniometry. In some embodiments, out-of-plane orientation (tilt) may be reduced using double reticles (spaced reticles that overlap looking vertically down when tilt is non-negligible), foam level indicators, or a combination thereof.

In some embodiments, the invention further comprises negative template (stamp) protrusions on the surface of the optical element in contact with the anterior surface of the cornea, wherein the negative template protrusions can produce changes in the volume of the treated stroma, including but not limited to increased corneal stroma densification, increased vitrification, and changes in the corneal stroma mechanical properties during the Photovitrification (PV) process. In some embodiments, the size of the reverse template projections is in the range of 5 to 200 μm, and these projections are located on the optical element to match the location of the PV treatment area on the cornea. In some embodiments, the reverse template enhances the impact of PV processing, including: a magnitude of a corneal change, a duration of corneal vitrification, or any combination thereof.

In some embodiments, the counter template (stamp) is a stamping solid, including an ocular solid in contact with the anterior surface of the corneaA reverse template projection on a rear surface of the fixture; these protrusions provide external stress on the cornea during the photo-vitrification (PV) process (Tx), which is also substantially equivalent in optical and thermal properties to the optical element material. In the case of sapphire as an optical material of an optical element and in which the chemical composition of sapphire is Al₂O₃In this case, the counter template protrusions may be sapphire or any other material that bonds well to the sapphire substrate, has similar optical properties to the sapphire substrate for efficient transmission of photon energy, and has similar thermal properties to the sapphire substrate for efficient heat removal from the cornea during PV Tx. The sapphire counter-template protrusions on the sapphire optical element can also be matched (i.e., have similar values) to the coefficient of thermal expansion needed to achieve good bonding under thermal cycling conditions. In some embodiments, the counter-template projections may have low photon scattering properties, such that photons are transmitted through the optical element and through the counter-template projections without significant scattering. In some embodiments, the reverse template projections may have substantial photon scattering properties such that photons are transmitted without scattering via the optical element but substantially scattered by propagation of the reverse template projections such that: expanding the spatial distribution of photons to increase the treatment (Tx) area, diffusing the spatial distribution of photons to "homogenize" the photo-irradiation over the Tx area, or any combination thereof.

In some embodiments, the counter-template projections on the optical element may be created by several suitable means, including but not limited to laser machining/ablation, machining, chemical etching, chemical vapor deposition, physical vapor deposition, sputtering, bonding an ultra-thin plate to the optical element, or any combination thereof.

In some embodiments, in addition to the devices of the invention, the invention employs at least one of the following diagnostic devices before, during and/or after treatment:

a-corneal topography and corneal tomography;

B-Optical Coherence Tomography (OCT) including epithelial thickness profile;

c-nonlinear microscopy including Second Harmonic Generation (SHG) imaging, Third Harmonic Generation (THG) imaging and two-photon excited fluorescence (TPEF) imaging to provide a complete analysis of epithelial, stromal-epithelial, stromal and endothelial effects;

d-confocal microscopy;

e-adaptive optics; and

f-test equipment suitable for measuring corneal mechanical properties (e.g., elastic modulus) including, but not limited to, Brillouin optical microscopy, quantitative ultrasound spectroscopy, corneal transient elastography, OCT elastography, and atomic force microscopy.

In some embodiments, the extent of each treatment (Tx) area on the cornea includes, but is not limited to, 0.2mm²To 100mm²Tx region in between. In some embodiments, the range of Heating Affected Zone (HAZ) depths for each Tx region includes, but is not limited to, HAZ depths between 20 μm and 300 μm for each Tx region. In some embodiments, the photon source energy range includes, but is not limited to, energies between 0.25W and 20W. In some embodiments, the photon output energy per pulse per Tx region ranges from, but is not limited to, between 200 millijoules (mJ) to 1000mJ per pulse per Tx region. In some embodiments, the per-pulse photon source duration range includes, but is not limited to, per-pulse photon source durations between 20 milliseconds (ms) and 2000 ms. In some embodiments, the photon source waveform comprises one or more pulses, wherein the pulse time interval ranges from, but is not limited to, a pulse interval between 10ms and 200 ms. In some embodiments, the thickness of the projections on the counter template range from, but is not limited to, a thickness between 5 μm and 200 μm. In some embodiments, the range of variation of the corneal optical aberrations includes, but is not limited to, a variation between 0.1 μm and 10 μm for each lower order aberration, a variation between 0.05 μm and 1.0 μm for each higher order aberration, and a variation between 0.05 μm and 1.0 μm for each aberration that cannot be predominantly (at least 51%) described by Zernike polynomials (and coefficients) up to and including the 8 th radial order. In some embodiments, the light is directed to the lensThe compensation range for the optical aberrations includes, but is not limited to, a compensation between 0.05 μm and 1.0 μm for each lens optical aberration.

In some embodiments of the invention, a method of using a device and/or system that can be used for in situ corneal Photovitrification (PV) of the cornea of a human eye in vivo, altering corneal structures and properties including, but not limited to, corneal optical aberrations, or any combination thereof, has at least the following exemplary steps:

a-instill a drop of local anesthetic (e.g., proparacaine without preservative) into the eye.

B-after the anesthetic has acted, a drop of solute-free lotion (e.g., distilled water) is instilled into the eye.

C-after step B, the eye fixation device and its accessories (suction ring, optics, tapered clip and ring illuminator) are placed on the eye.

D-after step C, the reticle on the optics is used for centering on the pupil center (or other centering reference).

E-after step D, the cornea is flattened by the optical element by applying an attractive force to the suction ring of the ocular fixture between the cornea and the optical element with the pneumatic injector.

F-after step E, the handpiece that is part of the fiber optic delivery subsystem is docked (docked) to the eye fixation device by the pre-aligned permanent magnet. The handpiece includes optical fibers that are pre-aligned in a predetermined PV processing (Tx) geometric arrangement (e.g., two concentric rings, each ring having 4 or 8 optical fibers).

G-after step F, the cornea is photo-irradiated for a period of, for example, 100 milliseconds, wherein PV Tx photons are transmitted through the optical fiber. In some embodiments, each PV Tx region is irradiated for 100 milliseconds. During each irradiation, the corneal surface is maintained within ± 5 degrees of the physiological corneal surface T (approximately at 35 ℃) during the photovitrification process while the anterior corneal stroma is heated to produce photovitrification.

H-after step G, removing the handpiece and eye fixation device from the eye.

In some embodiments, in accordance with the schematic of fig. 9, the inventive apparatus of the present invention can be configured such that at least two photon sources are independently controllable, as shown on an Optical bench (Optical Deck) in fig. 9, wherein each photon source is individually coupled to a separate Optical fiber in the fiber optic transmission subsystem. In some embodiments, the photon source may be an independently controllable Semiconductor Diode Laser (SDL). In fig. 9, each SDL is symbolized as a diode. In fig. 9, the following terminology is used: PCB-printed circuit board, I/O-input/output, TE-thermoelectric, and USB-universal serial bus. In some embodiments, the inventive apparatus of the present invention employs at least 2 to 48 individually controllable photon sources that are individually coupled to a single optical fiber in a fiber optic transmission system.

In some embodiments, at least 1,3, 5 or other odd number of independently controllable photon sources may be used. In some embodiments, the vector components associated with providing symmetric photo-irradiation of the cornea (to reduce the astigmatism that may be caused) may be adjusted for an odd number of photon sources. In some embodiments, the vector components may be adjusted for an even number of photon sources.

In some embodiments, a single laser array is located on one or more common Thermoelectric (TE) cooling plates for thermal control; in fig. 9, four TE cooling plates are shown (one plate for each set of four SDLs).

In some embodiments, the shutter shown in fig. 9 is used to vary the duration of corneal laser irradiation while SDL is continuously used in continuous (cw) mode. In some embodiments, the inventive devices of the present invention utilize SDLs in a pulsed mode, in which any one SDL is inactive (i.e., an "on/off" switch) before being activated by a pulsed current, instead of employing a shutter. In some embodiments, the inventive apparatus of the present invention utilizes a pulsed mode of SDL instead of employing a shutter, in which the SDL is in a "simmer mode" (active but below the current threshold at which lasing occurs) and then increased above the threshold by a pulsed current. In some embodiments, the inventive apparatus of the present invention utilizes an SDL in a variable pulse mode instead of employing a shutter, in which one or more SDL power outputs have predetermined waveforms including variable waveforms having at least one of the following variations, namely: the "ramping up" instantaneous power during irradiation, maintaining constant instantaneous power during irradiation, and controlling more complex instantaneous power output during irradiation.

In some embodiments of the inventive apparatus of the present invention, the beam from each photon source of the plurality of photon sources is coupled directly into its corresponding optical fiber, and the characteristics of the coupled beam are adjusted by the operating characteristics of the photon source itself. In some embodiments of inventive apparatus of the present invention, the beam from each photon source of the plurality of photon sources is also passed through at least one optical system (e.g., lens, mirror, etc.) that further conditions at least one characteristic of the beam before it reaches its corresponding optical fiber. In some embodiments, independent control of pulse duration in each photon source may also generate treatments to at least reduce astigmatism and other corneal diseases, including but not limited to keratoconus, other naturally occurring ectasias, and iatrogenic ectasias.

In some embodiments, the inventive apparatus of the present invention includes at least a microprocessor control board subsystem connected to a User Interface (UI) based laptop (or optionally to a tablet, iPad, or smartphone) via a Universal Serial Bus (USB). In some embodiments, the inventive apparatus of the present invention may employ a Microprocessor Board (MB) with a custom Interface Board (IB) attached. In some embodiments, the MB-IB control subsystem controls all photon sources, controls internal shutters (if necessary) and/or any additional interlocks, mediates and/or supervises firing (sparking) of the photon sources, and/or controls and supervises Direct Current (DC) power from a power supply to power the photon sources. Additionally, in some embodiments, the MB-IB subsystem controls, coordinates, and checks the calibration of the photon output. In some embodiments, the inventive devices of the present invention include at least a counter/activator subsystem that records the patient's photo-induced vitrification (PV) process (Tx), distinguishes between the PVTx and calibration points, and activates the paid and/or billed PV Tx.

In some embodiments, the inventive apparatus of the present invention includes at least software that drives a User Interface (UI). In some implementations, the UI receives operator input through a keyboard, touch screen, and/or voice recognition software. In some embodiments, the UI provides user settings not only for a light induced vitrification (PV) system, but also password protection, logging and/or archiving data for the user, and/or technical diagnostics and/or real time information for operation and maintenance of the system. In some embodiments, the UI uses patient eye measurements to determine the patient's treatment needs, including but not limited to detecting, tracking, and indicating eye imaging data for mounting eye fixtures and/or specifying and controlling the transmission of photon source energy into each fiber of a fiber optic transmission subsystem that produces at least one PV treatment.

In some embodiments, the User Interface (UI) is in the form of a touch screen control UI that is connected to the microprocessor board via a wired connection, a wireless Universal Serial Bus (USB) and/or bluetooth accessory, and/or to the internet. In some embodiments, the communication includes uploading patient records and/or video (after compression if necessary) onto a network server and/or downloading software updates and information from a network server. In some embodiments, the inventive apparatus of the present invention allows the user interface to be separated from the host processor, thereby isolating the task of setting up the program protocol and/or data archive from the direct operation of the inventive apparatus.

In some embodiments, the inventive devices of the present invention reduce cost and reduce complexity of the system. In some embodiments, because the discrete photon source may have separate output power monitoring, and separate associated channel control and monitoring at the far end of the fiber optic transmission subsystem, the delivery of the system calibration and resulting optical "dose" to the patient by the inventive apparatus of the present invention can be made more accurate and reproducible. In some embodiments, the inventive devices of the present invention allow a single photon source energy to be directed to each Photovitrification (PV) treatment (Tx) zone to at least affect (e.g., correct), reduce or alleviate/reduce the symptoms of astigmatism and other corneal diseases, including but not limited to keratoconus, other naturally occurring dilations, and iatrogenic dilations, as well as compensate for naturally occurring and iatrogenic corneal epithelial thickness changes. In some embodiments, a single photon source energy (and/or single photon source timing) can adjust the dose in each PV Tx region to overcome naturally occurring and iatrogenic corneal epithelial thickness variations, as the variations can be current pre-processing (pre-Tx), and can also change post-processing (post-Tx), as observed during other laser vision changes (e.g., optimization). In some embodiments, the present invention employs data that takes into account pre-treatment of epithelial thickness and post-Tx over time. In some embodiments, the present invention employs data that takes into account dosimetry of photon source energy radiation transmitted to the corneal stroma, which may be dependent on epithelial thickness; epithelial thickness variations can therefore be compensated by adjusting the laser energy at each PV Tx zone location. In some embodiments, the present invention employs data from optical and/or ultrasonic epithelial thickness analysis instruments to obtain an epithelial thickness map and use the epithelial thickness information to improve PV Tx.

In some embodiments, the inventive apparatus of the present invention employs a direct coupling of each photon source into each optical fiber, which allows for a reduction in the number of mechanical and optical components. In some embodiments, the inventive apparatus of the present invention allows for "drop-in" replacement of any photon source in an array. In some embodiments, the inventive apparatus of the present invention allows for "embedded" replacement of any fiber optic transmission subsystem.

In some embodiments, the inventive devices of the present invention operate according to the steps illustrated in fig. 10. The patient initially views a fixation light (fixation light) located on the visual axis defined by the telescopic line of sight shown on the monitor center (pre-alignment) of the inventive device. In some embodiments, the fixation may be substantially superior; viewing in a given direction (e.g., along the visual axis) is only necessary for the patient. In some embodiments, the steps of detecting, tracking and indicating centering, goniometric and normal incidence observation (normal incidenceviewing) are facilitated by an "induced beam" attached to the monitor, thereby compensating for small visual displacements relative to the visual axis.

In step 1 of fig. 10, eye imaging may be a real-time monitor display (on the screen of a computer portable device, such as iPad3, machine vision display, etc.), and optionally, input imaging from a separate device; the diagnostic data may be input from corneal topography, aberrational measurements, diopters, visual acuity, and/or other measurements. In some embodiments, the separate imaging device is a camera that records eye images.

In some embodiments, the inventive system of the present invention allows monocular viewing with, for example, iPad3, by using a telescopic finder scope (such as, but not limited to, an Orion telescope black 6X30 right angle correct imaging finder, which provides 6X magnification, and has a 30mm diameter objective with a 7 ° viewing angle). In some embodiments, a suitable finder mirror is mounted to iPad3 along the optical axis of the iPad3 camera. In some embodiments, the fixation lamp is also built into a suitable finder housing so that the patient's eye looks along the optical axis of the finder/camera. In some embodiments, a suitable finder mirror is pre-aligned along the optical axis, which is then used as a reference for fixation and mounting of the eye fixture assembly, such that the optical axis is at normal incidence (e.g., perpendicular) with respect to the optical elements of the eye fixture. In some embodiments, monocular viewing (as described above) plus normal incidence geometry is used to eliminate parallax (which may occur if the plane of the optic surface of the ocular fixture in contact with the cornea is not the same as the pupil "plane"). In some embodiments, the inventive system of the present invention further comprises dual reticles and/or level sensors for verifying/confirming normal incidence viewing. In some embodiments, a centering system equivalent to a double reticle is used to verify/confirm normal incidence viewing.

In step 2 of fig. 10, the photo-vitrification (PV) process (Tx) parameters are calculated from the diagnostic data; the characteristics of the inventive device (PV Tx energy and duration at each location) are automatically adjusted (using the PV Tx nomogram) to provide PV Tx parameters.

In step 3 of fig. 10, for centering, the pupil edge is found in 4 or more semi-meridians (e.g., at 0 °, 90 °, 180 °, and 270 °) in real time; the pupil center is the intersection of linear joints between opposing semi-meridians (e.g., 0 ° and 180 °). In some embodiments, the pupil center is a candidate centering reference point at which the "induced beam" can be projected onto the monitor. In some embodiments, in step 3, other choices of centering reference points may include the limbal center, the corneal vertex, and the coaxially observed corneal light reflection point (CSCLR). In some embodiments, in step 3, other reference "labels" may be used for goniometry, such as, but not limited to: iris images (iris patterns) and scleral vessels. In some embodiments, goniometric accuracy is necessary to treat symptoms of astigmatism. In some embodiments, the present invention uses a reference "marker" taken in the supine position, as the rotation of the eyeball occurs when the patient is transformed from the sitting up position to the supine position. In some embodiments, the inventive system of the present invention employs pupillometry with edge detection, comprising the steps of:

a-video recording eye (including pupil and limbus) imaging,

b-apply an edge detection algorithm (such as the Canny edge detector) to locate the pupil edge in a predetermined number of semi-meridians (e.g., in complete semi-meridians from 0 to 359 each),

c-ellipse fitting to the edge array, and

d-locate the center point of the ellipse, which is the pupil center.

By replacing the pupil edge in step B above with the limbus edge, the same procedure described above can be used to find the center of the limbus.

In step 4 of fig. 10, to assist the physician in installing the ocular fixation device, the present invention adds an "induction beam" (and angular indicia in the case of at least reducing or alleviating/reducing the symptoms of astigmatism) to the monitoring display. In some embodiments, the "induced beam" is displayed on a reference (such as the pupil center). In some embodiments, the reticle center-part eye fixture assembly-may be superimposed onto the "induced beam" as viewed on the display. In some embodiments, the angular indicia on the eye fixation device assembly may be superimposed onto the angular indicia shown on the display.

In step 5 of fig. 10, in some embodiments, the surgeon may install the eye fixation device assembly onto the eye. In step 5 of fig. 10, in some embodiments, machine vision is used to automatically manipulate the mechanical placement of the eye fixture assembly on the eye. Attractive forces are applied when the eye fixture assembly is properly installed (in terms of centering, goniometry and normal incidence-the latter is verified by the superposition of the cross or circles of the double reticle, thus reducing parallax; as an alternative, an electronic level sensor may be used to verify that the surface of the optical element in contact with the cornea is at normal incidence with the optical axis). If the eye fixture assembly is not properly installed, the attractive force is released and the installation procedure is repeated.

In step 6 of fig. 10, in some embodiments, the fiber optic transmission subsystem is docked to the installed eye fixture assembly; a set of permanent magnets allows the fiber optic transmission subsystem to be accurately aligned with respect to the eye fixation device. In some embodiments, the fiber optic transmission subsystem is manually docked by a physician. In some embodiments, the docking of the fiber optic transmission subsystem is automated. Once docked, a photo-vitrification (PV) process (Tx) is performed. In some embodiments, PV Tx is initiated manually by the physician. In some embodiments, PV Tx is automatically started.

In step 7 of fig. 10, in some embodiments, after the photo-vitrification (PV) process (Tx), the attractive force is released and the eye fixation device and fiber optic transmission subsystem are removed. In some embodiments, step 7 is performed manually. In some embodiments, step 7 is performed automatically.

In some embodiments, the inventive device/system of the present invention allows for complete automation of the entire process. In some embodiments, the inventive devices of the present invention utilize machine vision and pattern recognition for detecting, tracking, and indicating centering, goniometric, and normal incidence references. In some embodiments, the devices of the present invention utilizing an eye fixation device assembly are "locked to" an induced beam "target and mounted directly onto the target.

In some embodiments, once the eye fixation device assembly is properly installed, no detection, tracking, and indication is required; magnet-to-magnet interfacing of the fiber optic delivery subsystem to the eye fixture assembly provides accurate alignment of the photo-vitrification (PV) process (Tx) geometry placement on the cornea. In some embodiments, once the eye fixation device assembly is installed, small movements of the patient's eye are not important.

In some embodiments, the alignment mechanism/apparatus of the present invention is designed to achieve centering of a specific photo-vitrification (PV) process (Tx) geometry to achieve maximum and predictable utility of the inventive process utilizing the inventive apparatus of the present invention. In some embodiments, the inventive devices of the present invention utilize at least one of the following centering positions:

a-the Pupil Center (PC),

B-Corneal Vertex (CV),

c-any other suitable centered reference position, such as the corneal light reflection point (CSCLR) for coaxial viewing of patients with significant Kappa Angle (Angle Kappa).

In some embodiments, the inventive devices of the present invention allow for accurate and quick installation of them, such as ocular fixation devices, without the occurrence of repeated trauma to the cornea caused by multiple installation attempts and/or excessive installation adjustment. Fig. 11 shows one eye with CSCLR (first purkinje spot; marked by a white cross) as centering reference. PC (under light conditions; marked by a green cross almost overlapping with a white cross;) shifts X0.145 mm and Y0.021 mm relative to CSCLR. The figure also shows a computer-generated edge finding circle (yellow-limbus, green-pupil).

In some embodiments, the inventive apparatus of the present invention allows for the display of an "inducement beam" on the eye image on the pupil center PC and/or some other centered reference to "induce" the physician to (home in) his/her installation target. In some embodiments, the pupil (or limbus) edge is not displayed as shown in fig. 11. In some embodiments, it is sufficient to obtain a small number of pupil edge points (perhaps only 4 points at 0 °, 90 °, 180 °, and 270 °) to calculate the pupil center. In some embodiments, the "induced light beam" on the PC is a blinking red light or other visible target.

In some embodiments, the inventive devices of the present invention also utilize at least the following additional centering means, but are not limited to:

an A-camera and display with a telescope and a fixation lamp on the optical axis and at optical infinity,

a guide ring on the B-video display that matches the imaging dimensions of the eye-holder assembly, an

C-double reticles (one at or near the plane of the proximal face of the optical element of the eye-fixation device and the other at a distance of at least 1mm from the distal face of the optical element of the eye-fixation device) are used to avoid parallax-to-reticle separations as large as possible, but not exceeding the depth of field of the telescopic optics.

In some embodiments, the inventive devices of the present invention allow the eye fixation device assembly to be accurately mounted with respect to the angular orientation of the photo-vitrification (PV) treatment (Tx) geometry, allowing multiple PV Tx to be performed sequentially over time. For example, the patient may undergo primary PV Tx followed by secondary PV Tx. In some embodiments, the geometric arrangement of the primary and secondary PV Tx do not overlap; for example, if the primary PV Tx geometry includes PV Txs along the 0 ° -180 ° and 90 ° -270 ° meridians, then the secondary PV Tx geometry is oriented to PV Txs along the 45 ° -225 ° and 135 ° -315 ° meridians. In some embodiments, the primary and at least one non-primary PV Tx may substantially overlap.

In some embodiments, accurate goniometry affects (e.g., reduces or alleviates/reduces) at least the symptoms of astigmatism. In some embodiments, the present invention accounts for one or more complicating factors, such as eye rotation that occurs when a patient is lying down. In some embodiments, the inventive devices of the present invention utilize iris localization to define the angular orientation on the iris with respect to the fixed mark. In some embodiments, one or more secondary "induction beams" (in addition to the primary "induction beam" on the computer monitor or other centering reference) are included on the video display to assist the surgeon in accurately mounting the eye fixture assembly for centering and goniometry.

In some embodiments, the inventive devices of the present invention measure the position of the pupil center, corneal vertex, iris mark, etc. using a diagnostic device such as an aberrometer or corneal topographer. In some embodiments, the centering and goniometric data is then communicated by the software of the diagnostic device to some inventive devices of the present invention for performing a light induced vitrification (PV) process (Tx).

In some embodiments, the use of the attraction is automated. In some embodiments, the automated installation of the eye fixation device assembly may include optically detecting a meniscus (meniscus) edge formed by a fluid located between an optical element of the eye fixation device and the eye; when the meniscus is sufficiently extended, the electronic control may activate a predetermined amount of suction (such as 30cm Hg differential). In some embodiments, the inventive system of the present invention may utilize edge finding of the meniscus edge through the same or similar suitable type of process employed in pupillometry (e.g., pupillometry with edge finding as described above).

In some embodiments, the inventive systems of the present disclosure may utilize any other suitable system/device that optionally detects/measures meniscus photovitrification without adding complexity and/or without significantly increasing (e.g., doubling) the time of the inventive Photovitrification (PV) process (Tx) method.

In some embodiments, if the eye fixation device assembly is not properly installed, the attractive force may be released and the installation steps described above may be repeated.

In some embodiments, an eye fixation device having a thermally conductive optical element in contact with the anterior corneal surface provides a temperature within ± 5 degrees of the physiological corneal surface T (approximately at 35 ℃) during a light induced vitrification (PV) process (Tx) to improve the accuracy and predictability of the PV Tx. In general, the temperature of the surface of the eye can vary considerably from patient to patient. In some embodiments, the treatment of the present invention relies at least in part on the thermal history of laser heating, and thus, changes in the initial temperature of the eye (e.g., the anterior cornea) can alter the PV Tx effect. The optical elements of the ocular fixation device have sufficient thermal capacity and heat diffusion between the cornea and are sufficiently effective and rapid to provide a temperature within ± 5 degrees of the physiological corneal surface temperature (approximately 35 ℃) during the photovitrification process.

In some embodiments, the inventive devices/systems of the present invention provide for temperature within ± 5 degrees of the physiological corneal surface temperature (approximately 35 ℃) during a photovitrification process by continuously and/or periodically measuring the optical element temperature using one or more suitable techniques/devices, such as a non-contact radiometer or other suitable device, wherein the Tcontrol device is a resistive heater or other suitable device containing a Tmeasure in a feedback loop for thermostatically controlling the temperature of the optical elements of the ocular fixation device in contact with the anterior corneal surface.

In some embodiments, the inventive devices/systems of the present invention provide temperatures within ± 5 degrees of the physiological corneal surface temperature (approximately at 35 ℃) during the photovitrification process by further including measurements of changes in room temperature (generally, room temperature is different in each clinic and/or different at various times in one clinic).

In some embodiments, the inventive devices/systems of the present invention utilize a feedback loop mechanism by continuously or periodically collecting temperature measurements of at least one of the following temperatures: eye surface temperature, optical element temperature, and room temperature; by, for example, performing at least one of the following acts, but not limited to: the temperature of the optical elements of the eye fixation device is adjusted based on the obtained measurements by blowing hot air, by resistively heating the optical elements of the eye fixation device, for example, using a polyimide resistive heating tape in thermal contact with the optical elements of the eye fixation device, and other similar suitable methods.

In some embodiments, the present invention is directed to a geometric arrangement for performing a Photovitrification (PV) process (Tx) that utilizes photo-irradiation to vitrify the stromal tissue volume of the cornea and alter the structure and properties of the cornea, including but not limited to elastic modulus and optical aberrations-a process known as Photovitreokeratoplasty (PVK). In some embodiments, the inventive geometric arrangement of the present invention, which increases its refractive power by steepening the central cornea, may be used to correct or at least reduce hyperopia (aka hyperopia); reducing the power of the central cornea by flattening it can be used to correct or at least reduce myopia (aka myopia); by an axisymmetric and/or asymmetric PV Tx geometry arrangement, can be used to correct or at least alleviate symptoms associated with regular astigmatism and other corneal diseases (including but not limited to keratoconus, other naturally occurring ectasias, and iatrogenic ectasias); and by producing simultaneous visual acuity and increased depth of field at multiple distances (near, medium and far) can be used to alleviate/reduce the symptoms of age-related focal dysfunction. In some embodiments, as described in detail below, the inventive geometric arrangements of the present invention can be used to minimize corneal epithelial remodeling. In some embodiments, specific Tx geometries, including but not limited to those shown in fig. 12A to 12D and 13, can be used for specific inactive indications, including but not limited to at least reducing hyperopia (fig. 12A, 12C and 13), correcting or at least reducing myopia (fig. 12B and 12D), and alleviating/reducing symptoms of age-related focal dysfunction (fig. 12A to 12D and 13).

In some embodiments, the light-induced vitrification (PV) treatment (Tx) region, PV Heating Affected Zone (HAZ), PV Tx geometry, and PV Tx conditions may be optimized for applications of the light-induced vitrification (PV) treatment (Tx), including but not limited to reducing refractive errors of myopia, hyperopia, and regular astigmatism; producing synchronous near, intermediate and far vision; reducing irregular astigmatism and other corneal abnormalities, including but not limited to keratoconus and other naturally occurring and iatrogenic ectasias; changing Low Order Aberrations (LOA), High Order Aberrations (HOA), other aberrations that cannot be predominantly (at least 51%) described by Zernike polynomials (and coefficients) up to and including the 8 th radial order; altering corneal mechanical properties, or any combination thereof. In some embodiments, the geometric arrangement of the photo-vitrification (PV) treatment (Tx) area, the PV heating affected area (HAZ), and the entire PV Tx may be tailored to match specific indications to be used. In some embodiments, the PV Tx conditions are adjusted not only with respect to PV Tx area, PV HAZ, and PV Tx geometry, but also with respect to other parameters including, but not limited to, radiation wavelength, output shape, time-dependent pulse distribution (i.e., pulse shape) per pulse, time-dependent pulse sequence in the case of multiple pulses, energy per pulse, and presence or absence of inverse templates. In some embodiments, the PV Tx area, PVHAZ, PV Tx geometry, and other PV Tx conditions vary greatly for a number of reasons related to, but not limited to, the following factors: the type and magnitude of ocular optical aberrations; the type, extent and location of corneal disease; there is a need for improved visual acuity type (near, intermediate, far, or any combination thereof) and magnitude, duration of effect, type and magnitude of favorable corneal stromal changes that are improved as much as possible, and type and magnitude of undesirable adverse side effects that are reduced as much as possible.

In some embodiments, the adjusting of the photo-vitrification (PV) process (Tx) region includes adjusting involving one or more of the following features: size, shape, location (i.e., r, θ coordinates in terms of radial and angular parameters), orientation, gradient, smoothness, or any combination thereof; wherein the corneal surface curvature gradient is reduced to 3 diopters (D) per millimeter (mm) or less than 3 diopters per millimeter (≦ 3D/mm), wherein the smoothness is the surface Root Mean Square (RMS) roughness in each PV Tx region, which is reduced to 10 μm or less. In some embodiments, all of the PV Tx regions have the same features of size, shape, location, orientation, gradient, and roughness, so as to produce a symmetric PV Tx. In some embodiments, at least one PV Tx region has different characteristics compared to other PV Tx regions in order to produce asymmetric PV Tx.

In some embodiments, the photo-vitrification (PV) processing (Tx) area size may be in the range of 0.2 to 100mm²Wherein the PV Tx area size refers to the anterior corneal surface area contained within a perimeter (perimeter) defined by a full width at half maximum (FWHM) intensity (I)_max,ave/2) locus of points, wherein I_max,aveIs the average maximum intensity of photon output in an output pulse [ unit: watt per square meter (W/m)²)]. In some embodiments, the at least one PV Tx region may have a shape selected from the group consisting of: circular, overlapping circular, elliptical, oval, stadium, polygonal with rounded corners, arc, circular, or any combination thereof. In each case, I_max,aveThe locus of/2 points defines the size of the PV Tx region. Because the cornea has a convex curvature, the protrusion of the plateau toward the cornea has a larger area at the corneal surface.

In some embodiments, the location and orientation of the light-induced vitrification (PV) treatment (Tx) zone and PV Tx geometry may be configured to modify corneal structures and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof with beneficial effects, including but not limited to ametropia to mitigate myopia, hyperopia, and regular astigmatism; producing synchronous near, intermediate and far vision; reducing irregular astigmatism and other corneal diseases, including but not limited to keratoconus and other naturally occurring and iatrogenic ectasias; changing Low Order Aberrations (LOA), changing High Order Aberrations (HOA), changing other optical aberrations that cannot be predominantly (at least 51%) represented by Zernike polynomials (and their coefficients), changing mechanical properties, or any combination thereof.

In some embodiments, the devices and processes for altering corneal structures and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof, comprise accounting for the results of short-term (immediate) and delayed (including long-term) light-induced vitrification (PV) treatments (Tx), to provide long-term (aged) changes to corneal structures and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination of effects thereof, including but not limited to ametropia reduction and other beneficial results listed above, and also to provide optimal binocular vision while eliminating or reducing clinically significant side effects, such side effects include, but are not limited to, induced ocular disorders (e.g., night vision disorders, glare disability, etc.) and induced ocular discomfort and tear dysfunction syndrome. For example, in some embodiments, long-term changes in corneal structure and properties (including, but not limited to, corneal optical aberrations, corneal elastic modulus, or any combination of effects thereof) can be achieved in part by reducing the recovery of changes in corneal structure and properties, including, but not limited to, changes in corneal optical aberrations due to post-Tx epithelial remodeling (e.g., epithelial changes such as epithelial hyperplasia). post-Tx epithelial changes caused by epithelial thickening can occur at "packed" reentrant corneal surface irregularities; in contrast, post-Tx epithelial remodeling by epithelial thinning may occur throughout the lobe membrane surface irregularities. In some embodiments, the PV Tx region, PV HAZ, PV Tx geometry, and PV Tx conditions are configured to produce a smoother, lower corneal curvature gradient than that produced by previous devices and methods. Corneal topography measurements can be used to measure corneal curvature gradients and smoothness.

In some embodiments, the present invention includes a time coordinate (t), which may refer to the time at which photo-irradiation begins. In some embodiments, the photo-vitrification (PV) process (Tx) includes at least one of: (A) a photoinduced irradiance profile within two spatial coordinates (r, theta) of each PV Tx zone on the anterior cornea, (B) an overall PV Tx geometric arrangement of PV Tx zones, (C) three spatial coordinates (r, theta, z) of each PV Tx heating-affected zone (HAZ) that includes a densified corneal stromal tissue volume, (D) a time-dependent waveform of photoinduced irradiation (e.g., photoinduced irradiance versus time), (E) a thermal history profile within the PV HAZ, (F) an external stress applied to each PV Tx zone by a Reverse Template (RT), and/or (G) a phenomenology (e.g., velocity and mechanism) of corneal stromal changes resulting from the thermal history profile within the PV HAZ that is associated with a favorable effect of increasing changes in corneal structure and properties (including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof) while reducing an undesirable effect, such as collateral damage to the cornea, including but not limited to the anterior Basement Membrane (BM) and to corneal cells (Ks). In some embodiments of the invention, the PV Tx conditions are such that Ks is maximally quiescent, while minimizing the formation and activity of fibroblast phenotypes.

In some embodiments, the thermal history profile within the Heat Affected Zone (HAZ) of the Photovitrification (PV) -item E above-is affected by at least one of: (A) the photoinduced irradiance distribution within two spatial coordinates (r, θ) of each PV treatment (Tx) area on the anterior cornea, (B) the overall PV Tx geometry of the PV Tx areas, (C) the three spatial coordinates (r, θ, z) of each PV HAZ (comprising a densified corneal stromal tissue volume), and (D) the time-dependent waveform of the photoinduced irradiation (e.g., photoinduced irradiance versus time). In some embodiments, the thermal history profile within the PV HAZ is also affected by at least one of: (H) the photo-irradiation wavelength (for which the corneal epithelium and corneal stroma have temperature-dependent absorption coefficients) and (I) three types of Thermal Diffusion (TD): (I1) TD within the PV Tx zone and PV HAZ of the cornea, (I2) TD radially and axially from the PV Tx zone and PV HAZ into the surrounding tissue, and (I3) TD axially from the cornea into the optical elements of the ocular fixation device.

In some embodiments, a particular photo-irradiation waveform produces enhanced targeting of the anterior corneal stroma while minimizing adverse effects on corneal tissue that is not intended to be part of a Photovitrification (PV) Heating Affected Zone (HAZ) that produces changes in corneal structure and properties, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination thereof.

In some embodiments, the improvement in corneal structure and property changes, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination of their effects, is related to (a) the distribution of photo-induced irradiance within two spatial coordinates (r, θ) of each photo-vitrification (PV) treatment (Tx) zone on the anterior cornea and (C) three spatial coordinates (r, θ, z) of each PV HAZ, as described above. In some embodiments, the use of a reverse template to enhance the vitrification change to each PV treated volume produces enhanced stromal corneal densification resulting in increased magnitude and duration of corneal structure and property changes, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination of effects thereof.

In some embodiments, fig. 12A to 12D show examples of photo-vitrification (PV) process (Tx) geometries with the position and orientation of the PV Tx region that can be used for alteration of corneal structures and properties including, but not limited to, corneal optical aberrations, corneal elastic modulus, or any combination thereof. All of the PV Tx zones in the example of fig. 12A to 12D are continuous PV Tx zones in four semi-meridians instead of a discontinuous set of PV Tx zones in each semi-meridian. Fig. 12A and 12B show an elliptical PV Tx area having a major axis (12A) aligned with semi-meridians or a major axis (12B) aligned perpendicular to semi-meridians. Fig. 12C and 12D show rectangular PV Tx areas aligned along (12C) or perpendicular to (12D) semi-meridians of 0 °, 90 °, 180 °, and 270 °. In some embodiments, the continuous PV Tx region and PV Tx geometry arrangement shown in fig. 12A to 12D is used for alteration of corneal structures and properties including, but not limited to, corneal optical aberrations, corneal elastic modulus, or any combination thereof.

Fig. 13 shows another example of a photo-vitrification (PV) process (Tx) geometry arrangement, with the position and orientation of the PV Tx region, that can be used for modification of corneal structures and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof. All of the PV Tx regions in the example of fig. 13 are continuous elliptical PV Tx regions, with the PV Tx distribution peaking at the center of the PV Tx region and then tapering off with distance from the center to provide a smooth gradient of corneal curvature change within the PV Tx region. In some embodiments, the PV Tx region with large radius and smoothly graded corneal curvature variation and the geometric arrangement of the PV Tx shown in fig. 13 are used for modification of corneal structures and properties including, but not limited to, corneal optical aberrations, corneal elastic modulus, or any combination thereof.

In some embodiments, the gradient of corneal curvature change (and thus gradient of refractive change) and corneal surface roughness are reduced to reduce epithelial changes. In some embodiments, the angular segments (also referred to as "angular domains") are "blended" with each other using a gradient of refractive change that provides a "transition zone. For example, fig. 14A and 14B illustrate the difference between the "step function" of refractive change (fig. 14A) and the current description of the "mixed" gradient of refractive change in the "transition zone" (fig. 14B). In one embodiment, fig. 14B shows refractive change (D: diopter) versus (vs.) semi-meridian for a quadruple photo-induced vitrification (PV) treatment (Tx) geometry. In some embodiments, the corneal curvature gradient between and within at least one of the following locations is in the range of 0.1 to 3 diopters (D) per millimeter: an angle segment, a diameter segment, or any combination thereof.

In some embodiments, the refractive change "step function" as shown in figure 14A is actually a multiple "bifocal" design, having maxima at 90 °, 180 °, 270 °, and 360 ° (360 ° is the same as 0 °) that are 3 diopters (D) more than the minima at 45 °, 135 °, 225 °, and 315 °; the maximum has a greater refraction to provide functional near vision, while the minimum has no additional refraction and is used for functional distance vision by emmetropic patients with age-related focal dysfunction. In one embodiment, refractive changes over a 3 diopter (D) range are shown in fig. 14A and 14B. In some embodiments, the range of refractive change may be reduced for eyes with low myopia. In some embodiments, the range of refractive change is increased. In some embodiments, the multiple "step function" design is similar to a discontinuous refractive design for bifocal intraocular lenses, spectacles, and/or contact lenses. In some embodiments, a trifocal design is used to provide functional intermediate distance vision (in addition to near and distance vision). In some embodiments, the multiple "sigmoid function" design as shown in fig. 14B is a multifocal design, with considerable "weight" at near-maximum and minimum semi-meridians, but with additional multiple focalization over the entire range including those diopter increases ("ads") for functional intermediate distance vision. In some embodiments, multiple "sigmoid function" designs are similar to refractive changes used for progressive lens eyeglasses and contact lenses and provide functional intermediate distance vision. In some embodiments, other oscillation functions, such as sinusoidal functions, may be used.

Other geometric arrangements of "mixed" gradients of refractive changes within the "transition zone" can be used to at least reduce symptoms associated with astigmatism and/or to adjust the light induced vitrification (PV) treatment (Tx) to compensate for naturally occurring and iatrogenic epithelial thickness changes. Fig. 15A and 15B show PV Tx geometry examples that can be used to at least reduce regular astigmatism (15A) and to provide unequal treatment energy density to compensate for epithelial thickness variations (15B). In some embodiments, fig. 15A and 15B show refractive change (D: diopter) versus (vs.) semi-meridian for a quadruple PV Tx geometry, which is used in two applications: fig. 15A shows the PV Tx energy density geometric distribution affecting regular astigmatism (i.e., at least reducing normal astigmatism), and fig. 15B shows the unequal PV Tx energy density geometric arrangement to compensate for epithelial thickness variation.

In some embodiments, in the regular astigmatic Photovitrification (PV) process (Tx) example (fig. 15A), the PV Tx energy density is intended to produce a 3 diopter (D) variation at 90 ° and 270 °, but only a 2D variation at 180 ° and 360 °. This regular astigmatic PV Tx geometry is used both to alleviate/reduce the 1 diopter (D) symptoms of pre-Tx regular astigmatism (with a straight meridian along the 90/270 axis) and to provide simultaneous functional distance, intermediate and near visual acuity. In some embodiments, the regular astigmatic PV Tx geometry may have only two maxima and two minima, instead of the quadruple PV Tx geometry shown in fig. 15A.

In some embodiments, fig. 15B illustrates compensation for naturally occurring and iatrogenic variations in epithelial thickness; although unequal PV Tx energy densities are used, it is contemplated that the photo-vitrification (PV) process (Tx) has a desired number of pure spheres to produce a refractive change of between 2.5 and 3.0 without a change in the thickness of the epithelium. The corneal epithelial thickness is different in each eye and also different in different regions of each eye. In some embodiments, on average, the superior (e.g., 90 °) corneal epithelium is thinnest, while the inferior (e.g., 270 °) corneal epithelium is thickest. On average, the nasal and temporal corneal locations (left eye-OS 180 ° and 360 ° respectively; right eye-OD opposite) had moderate epithelial thickness. The epithelium absorbs the laser energy but is not used for corneal stromal vitrification. Variations in corneal epithelium thickness cause unequal variations in the amount of radiation-i.e., the photon "dose" to the corneal stroma. In some embodiments, the PV Tx energy density is adjusted to compensate for the effect of epithelial thickness on the amount of radiation in each PV Tx region; epithelial thickness variation can be measured by optical coherence tomography and high frequency ultrasound biomicroscopy. In some embodiments, the need for PV Tx energy density modulation may be altered by using external stress applied by the opposing template. In some embodiments, the reverse template may include at least one projection protruding from an optical element of the eye fixation device in contact with the anterior corneal surface and contacting the PV Tx region; the projections have a thickness in the range of 10 to 100 μm.

In some embodiments, the gradual corneal curvature gradient change and gradual refractive change and reduced corneal surface roughness reduce posterior-Tx epithelial changes that result in restoration of changes in corneal structure and properties (including but not limited to corneal optical aberrations, or any combination of their effects). Generally, after refractive surgery, epithelial changes occur, thereby reducing corneal surface irregularities and thereby restoring a smooth anterior corneal surface; this post-Tx epithelial alteration is a major factor in the restoration of altered corneal structure and properties, including but not limited to corneal optical aberrations, or any combination of their effects. The "step function" refractive changes shown in figure 14A promote extensive and rapid epithelial changes for a "smooth over" irregular surface. In some embodiments, the "sigmoid" function refractive changes shown in figure 14B reduce the recovery of epithelial changes and changes in corneal structure and properties (including but not limited to corneal optical aberrations, or any combination thereof).

In some embodiments, the surface Root Mean Square (RMS) roughness of each PV Tx area is reduced to 10 μm or less. In some embodiments, the corneal surface curvature gradient is reduced to 3 diopters (D) per millimeter (mm) or less (≦ 3D/mm).

In some embodiments, the smoother refractive changes (and thus smoother and lower magnitude corneal surface curvature gradients) associated with the sigmoid functions shown in fig. 14B, 15A, and 15B may result in fewer and slower changes in the epithelium than the "step function" example in fig. 14A. In some embodiments, the detailed refractive change (in terms of the sector width of the maxima and minima of the sigmoid function and the corneal curvature gradient) can be adjusted by specification (specification) of the Photovitrification (PV) treatment (Tx) zone, the PV Heating Affected Zone (HAZ), the PV Tx geometry, and the PV Tx conditions. In some embodiments, the detailed refractive change can be adjusted to optimize the effects of changes in corneal optical aberrations. In some embodiments, as a design goal, the configuration of the complete shape (length, width, and depth), thermal history, and PVTx geometry of the PV HAZ, as far as possible enhances targeted beneficial effects, including but not limited to changes in corneal structure and properties (including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof), and minimizes deleterious effects, including but not limited to damage to corneal structures and restoration of changes in corneal structure and properties (including corneal optical aberrations, or any combination thereof).

In one embodiment, one example of the dimensions of a photo-vitrification (PV) process (Tx) area is schematically shown in fig. 13, which is a quadruple PV Tx geometry. In some embodiments, each PV Tx area is elliptical, each PV Heating Affected Zone (HAZ) has a depth difference, the deepest portion being located at the center of each PV Tx area; the center of the PV Tx region is on the semi-meridians of 90 °, 180 °, 270 ° and 360 °, and thus corresponds to the maximum value in fig. 14B. In some embodiments, the PV HAZ depth (and the magnitude of corneal optical aberration changes and refractive changes) is graded from the center of the PV Tx regions and decreases with distance away from the center of each Tx region. In some embodiments, the dimensions of the PV Tx region and the PV HAZ, including the depth of the full width at half maximum (FWHM), may be different. In some embodiments, the shape of the PV Tx region may be selected from the group consisting of, or is not limited to: circular, elliptical, oval, stadium, polygonal with rounded corners, arc, circular, or any combination thereof. In some embodiments, different numbers of PV HAZs having specific shapes and volumes (i.e., r, θ, z dimensions) in specific PV Tx geometries and photo-irradiation using specific PV Tx conditions, with or without inverse templates during PV Tx to provide external stress, may also be used to optimize targeted beneficial effects including, but not limited to, changes in corneal stromal structure and properties (including, but not limited to, corneal optical aberrations), and may also be used to minimize deleterious effects including, but not limited to, damage to corneal structures and restoration of changes in corneal structure and properties (including, but not limited to, corneal elastic modulus and corneal optical aberrations, or any combination thereof).

In some embodiments, due to the complex biomechanics of the cornea, the Photovitrification (PV) treatment (Tx) produces localized PV Heating Affected Zones (HAZ) and non-localized changes to corneal structures and properties, including but not limited to corneal elastic modulus and corneal optical aberrations, or any combination thereof. In one embodiment, while the PV HAZ is shown in fig. 13 as being located at the periphery of the cornea, changes in corneal structure and properties (including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof) may extend to the center of the cornea. In one embodiment, figure 13 shows a quadruple PVTx geometry in which concentric rings are 1mm apart in diameter and centered with respect to the via center (or with respect to another pair of references, such as corneal light reflection for coaxial viewing). In one embodiment, fig. 13 shows a gradual progression of the PV Tx area and accompanying PV HAZ, schematically represented by shading, i.e. the darker the shade colour, the deeper the PV HAZ, the greater the change in corneal structure and properties.

In some embodiments, the present invention creates a Photovitrification (PV) Heating Affected Zone (HAZ) that is axisymmetrically arranged centered about the pupil center (or another reference in the pair) to minimize the occurrence of induced astigmatism. In some embodiments, the PV treatment (Tx) energy density within each PV Tx zone is adjusted to compensate for epithelial thickness variations, thereby minimizing the occurrence of induced astigmatism and/or reducing the symptoms of astigmatism. In some embodiments, the polar coordinates r, θ of each PV Tx region are adjusted to compensate for epithelial thickness variations and pre-Tx astigmatism.

In some embodiments, figures 13, 14A, 14B, 15A, and 15B are examples of symmetric quadruple Tx geometric arrangements of corneal curvature (and thus corneal refraction) changes. In some embodiments, Tx geometries, such as symmetric two-fold, six-fold, eight-fold, ten-fold, twelve-fold Tx geometries, are used for alteration of corneal structures and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination thereof. In some embodiments, asymmetric and/or odd-weighted (e.g., single Tx region and triple and quintuple Tx regions) Tx geometries may be used.

In some embodiments, the present invention utilizes different sizes of Photovitrification (PV) Heating Affected Zones (HAZ). In one embodiment, fig. 16 shows a cross-section through two PV HAZs, which are bodies of revolution having approximately equal volumes: wherein the solid line is a "deeper" PV HAZ1 having a base [ at 0 μm at the corneal stroma (S) z ] of about 350 μm in diameter and extending to a depth of about 90 μm z, and wherein the dotted line is a "shallower" PV HAZ2 having a base [ at 0 μm at z of S ] of about 500 μm in diameter and extending to a depth of about 45 μm z. Fig. 16 shows a solid line, which is a cross-section related to the PV HAZ1, and a dashed line, which is a cross-section related to the PV HAZ 2. In fig. 16, the radial coordinate is compressed relative to the depth coordinate. In one embodiment, fig. 16 shows the dimensions of the PV HAZ2 adjusted to have twice the PV Tx area of the PV HAZ1 (at z 0 μm) and almost the same volume as the PV HAZ 1. In some embodiments, the systems of the present invention comprise a quasi-CW photon output, wherein the quasi-CW photon output can comprise single and/or multiple pulse energies, wherein the instantaneous power of each pulse can be constant or non-constant with a time-dependent waveform change that varies the instantaneous power.

In some embodiments, the area of Photovitrification (PV) Heating Affected (HAZ) is increased, the PV HAZ depth is decreased, and the corneal curvature gradient is decreased while maintaining dramatic changes in corneal structure and properties, including but not limited to corneal optical aberrations, corneal elastic modulus, or any combination of effects thereof. In some embodiments, these changes reduce epithelial alterations and exhibit improved efficiency, as decreasing anterior stromal depth targets more interwoven collagen sheets (see fig. 4) that have a greater biomechanical impact in producing alterations including, but not limited to, corneal optical aberrations, corneal elastic modulus, or any combination thereof.

In some embodiments, a Photovitrification (PV) Heating Affected Zone (HAZ) increases in area by increasing the area of the cornea that is photo-irradiated. In some embodiments, one means for increasing the area is a thermally conductive optical element located between the fiber tips (and/or between any optical elements for changing the distribution of photons emerging from the fiber tips), adjustable spacers (spacers), and ocular fixation devices in contact with the cornea. In some embodiments, the spacing of the optical transmission element relative to the optical element of the ocular fixation device may be automatically adjusted as described in detail in processing nomograms to obtain a predetermined amount of change in corneal optical aberration and/or to specify the processing of a particular indication for use (IFU).

In some embodiments, the output from the optical fiber may be altered by additional optical devices including, but not limited to: a cylindrical lens, a Powell lens (a type of aspheric lens), a axicon lens, or any combination thereof, to produce a shape of a particular photo-vitrified (PV) processed (Tx) region. In some embodiments, Powell lenses are manufactured with different "fan angles" to produce different "line" lengths. In some embodiments, the "line" length is increased by increasing the spacing of the flat (exit) faces of the lenses from the substrate. In some embodiments, custom Powell microlenses are fabricated using a transparent material (e.g., low OH silica) and are mounted in an assembly that juxtaposes the lens with the optical fiber, creating a Tx geometry. In some embodiments, the cylindrical lens produces a non-uniform (gaussian) radiation distribution, while the Powell lens produces a uniform radiation distribution within the in-line (rectangular) segment.

In some embodiments, Powell lens Photovitrification (PV) treatment (Tx) of the area improves the Tx impactDiameter of a pipe To the direction ofAnd (4) distribution. In some embodiments, the PV Tx region has a gradual change in PV Tx impactAngle of rotationA distribution (e.g., as shown in fig. 14B, 15A, and 15B). In some embodiments, each PV Tx region can be configured to have a larger area (e.g., length and width) and thus reduced discontinuity, while having a shallower depth, reduced sag, and smoother corneal curvature gradient.

In some embodiments, at least one photon source may be used to generate photons for Photovitrification (PV) Tx. In some embodiments, at least one photon source and an associated fiber optic delivery subsystem may produce an improved PV Tx geometry with a graduated (e.g., smooth corneal curvature gradient) radial and angular light distribution. In some embodiments, inventive apparatus of the present invention may utilize at least one photon source, wherein its output beam is subsequently split into two or more "beamlets", wherein each "beamlet" is independently controlled. As an example, a continuous wave (cw) solid state laser including a host material doped with at least one lasing material may produce a collimated, low divergence beam. Samples are described below: (A) the laser beam is directed into a beam distribution system, and/or (B) the beam distribution system includes a shutter for providing a configured exposure time for the laser; a beam splitting optical system comprising one or more beam splitters for generating beamlets; beamlet steering (steering) and focusing optics for directing focused beamlet rays into the optical fiber; a displacement stage for moving the fiber array into position to receive the focused beamlets; a position controller for positioning the displacement stage, and (C) a beamlet attenuator and/or beamlet modulator for adjusting the amount of focused beamlet light directed into the optical fiber; these beamlet attenuators and/or adjusters may be independently controlled to adjust the predetermined number of beamlets directed into a single optical fiber.

In some embodiments, multiple photon sources, including but not limited to lasers, intense pulsed light sources, or any combination thereof, are used to maximize targeted favorable corneal stromal alterations, as well as minimize deleterious effects, such as damage to corneal structures. In some embodiments, all of the plurality of photon sources have substantially the same output characteristics, including but not limited to: wavelength, time-dependent waveform, and instantaneous power. In some embodiments, at least one of the plurality of photon sources has a different wavelength than at least one other photon source. In some embodiments, at least one of the plurality of photon sources has a different time-dependent waveform than at least one other photon source. In some embodiments, at least one of the plurality of photon sources has a different instantaneous power than at least one other photon source.

In some embodiments, the corneal curvature gradient may be reduced by altering the photo-irradiation profile such that the photo-vitrification (PV) Heating Affected Zone (HAZ) is increased in area and partially deformed by external stress applied to the PV HAZ by the opposing template.

In some embodiments, the depth of the region of Photovitrification (PV) heating influence (HAZ) can be reduced by increasing the absorption coefficient and/or changing the laser radiation waveform to a shorter duration of radiation. In some embodiments, more complex photo-irradiation waveforms are utilized by "ramping up" the photo-irradiance and/or by utilizing multiple photo-irradiation times. In some embodiments, a more complex photo-irradiation waveform increases the amount of PV Tx within the PV HAZ while avoiding collateral damage. In some embodiments, multiple laser wavelengths may be used in each Tx zone in order to extend the axial extent of the HAZ and to make the thermal history of the treated corneal stromal tissue more uniform in the axial coordinate. In some embodiments, the thermal history within the radial coordinate of each Tx region is made more uniform by utilizing a radiation profile including, but not limited to, a "flat top" profile, a super gaussian profile, a "donut" profile, or any combination thereof. In some embodiments, the PV HAZ depth may also be adjusted by the external stress and the amount of external stress resulting from applying with the opposing template.

In some embodiments, the photo-vitrification (PV) process (Tx) geometry can be automatically rotated in several ways, such as with an electromechanical actuator or a micro-Dove prism, such that the PV Tx region is centered at a predetermined semi-meridian, thereby rotating the fiber array about the z-axis (see fig. 2).

In some embodiments, the geometric arrangement of the entire photo-vitrification (PV) process (Tx) can be changed by using different arrays of optical fibers and/or by adjusting the optical fibers in one array. In some embodiments, the PV Tx geometry may be changed by automatically changing the centerline diameter of the PV Tx area ring using an electromechanical actuator detailed by the Tx nomogram, to obtain a predetermined amount of corneal optical aberration change or a predetermined scale of corneal property change and/or to specify the PV Tx for a particular inactive indication.

In some embodiments, the range of corneal curvature changes includes, but is not limited to, 0.1 to 20 diopters(D) Change in corneal curvature in between. In some embodiments, the corneal curvature gradient range includes, but is not limited to, a corneal curvature gradient of 0.1D/mm to 3D/mm. In some embodiments, the range of the photo-vitrification (PV) processing (Tx) area includes, but is not limited to, 0.2mm²To 100mm²The PV Tx region of (a). In some embodiments, corneal vitrification, including but not limited to photovitrification, can be used to change corneal curvature to a range including but not limited to 0.1 to 20 diopters. In some embodiments, corneal vitrification, including but not limited to photovitrification, can be used to stabilize, reduce, or any combination thereof, naturally occurring corneal ectasia; iatrogenic corneal ectasia; or any combination thereof; wherein the reduction of corneal ectasia comprises at least one local change to corneal curvature within at least one local area defined by r, theta coordinates, wherein the change in corneal curvature is between 0.10 diopter (D) to 20D.

In some embodiments, the invention comprises: a-corneal vitrification (including but not limited to Photovitrification (PV)) treatment (Tx) changes that affect Low Order Aberrations (LOA) (including tip, tilt, defocus, and astigmatism); B-PV Tx variation affecting Higher Order Aberrations (HOA) (including but not limited to spherical aberration, coma, trefoil, and/or higher order astigmatism); C-PV Tx variation affecting aberrations that cannot be described predominantly (at least 51%) by Zernike polynomials (and their coefficients) up to and including the 8 th radial order; and D-any combination thereof, thereby producing a change in corneal optical aberrations that affects (e.g., optimizes) functionally synchronized vision at all distances (near, intermediate, and far) and affects (e.g., improves) vision quality (in terms of quality metrics, including but not limited to contrast sensitivity and stereoscopic visual acuity). In some embodiments, the defocus is a LOA that is altered to affect (e.g., correct) or at least reduce spherical refractive error for myopia and hyperopia, magnify retinal imaging, or provide any combination of the foregoing. In some embodiments, astigmatism-both vertical and horizontal-is a LOA, which is altered to affect (e.g., correct) or at least mitigate regular astigmatism. In some embodiments, HOA (e.g., spherical-primary and secondary, coma and trefoil) is optimized to provide vision improvement (e.g., increased depth of field) to at least partially compensate for age-related focal dysfunction; other HOAs may also be represented by terms in the Zernike basis set for refractive variations including, for example, the gradations discussed in connection with fig. 14B, 15A and 15B. In some embodiments, the LOAs, HOAs (collectively, all HOAs represented by terms in the basis set of Zernike polynomials) and other aberrations that cannot be described primarily (at least 51%) by Zernike polynomials up to and including the 8 th radial order (and their coefficients) are modified in a complex manner so as to eliminate or at least alleviate vision deficiencies due to irregular corneal diseases, including but not limited to keratoconus, naturally occurring ectasia, and iatrogenic ectasia. In some embodiments, one or more of the LOA and HOA are modified to reposition the imaging on the retina. In some embodiments, the inventive apparatus and methods of the present invention are used to alter a LOA. In some embodiments, the inventive apparatus and methods of the present invention are used to change the defocused LOA. In some embodiments, the inventive apparatus and methods of the present invention are used to vary the LOA of vertical and horizontal astigmatism (cylinder). In some embodiments, the inventive apparatus and methods of the present invention are tailored to simultaneously change the LOA of defocus and vertical and horizontal astigmatism. In some embodiments, the inventive devices and methods of the present invention are customized to alter one or more HOAs (e.g., coma, trefoil, spherical-primary and secondary, and other HOAs), or any combination thereof.

In some embodiments, the inventive apparatus and methods of the present invention are tailored to alter one or more aberrations that cannot be described primarily (at least 51%) by Zernike polynomials (and their coefficients) up to and including the 8 th radial order.

In some embodiments, a simultaneous vision emulator with adaptive optics may be used to "personalize" the light induced vitrification (PV) process (Tx) for each eye to obtain improved binocular visual acuity for objects (photopic, mesopic, and/or scotopic) at all distances (near, intermediate, and far) and under all lighting conditions, and to obtain improved visual quality across other factors, including but not limited to: contrast sensitivity, stereoscopic acuity, glare-free illusion, modulus transfer function, point spread function, and Strehl ratio. In some embodiments, the PV Tx geometry may be adjusted to modify and/or customize and/or personalize the patient PV Tx to affect (e.g., optimize) the combination of LOAs, HOAs, and other aberrations that cannot be primarily (at least 51%) described by Zernike polynomials (and their coefficients) up to and including the 8 th radial order. In some embodiments, the variation of LOAs, HOAs, and other aberrations that cannot be primarily (at least 51%) described by Zernike polynomials (and their coefficients) up to and including the 8 th radial order is accomplished by photo-irradiation asymmetric PV Tx geometry using the apparatus of the present invention, wherein: the a-PV Tx regions are in an axisymmetric PV Tx geometry of an even number of PV Tx regions photo-irradiated with different PV Tx energies [ except for those differences in PV Tx energies to reduce regular astigmatism and to compensate for naturally occurring and iatrogenic epithelial thickness variations ], the B-PV Tx regions are in an asymmetric PV Tx geometry (either with an odd number of PV Tx regions, or an asymmetric PV Tx geometry with an even number of PV Tx regions), or any combination of the foregoing.

In some embodiments, an inverse template may be used to provide external stress to apply pressure to at least one processing (Tx) region during Photovitrification (PV) Tx. It will be appreciated by those skilled in the art that the present invention is distinct from orthokeratology (also known as orthokeratology or corneal refractive treatment) and related procedures (such as enzymatic orthokeratology) that involve changes in corneal epithelial topography without the creation of vitrified stromal tissue that alters optical aberrations. Orthokeratology includes and requires night-time contact lens wear, whereby a temporary effect on optical aberration dissipation is obtained during the day after night-time contact lens wear. Rather, in some embodiments, the present invention produces corneal stromal changes that include vitrified corneal stromal tissue having altered structure and properties, including increased corneal elastic modulus and increased stromal densification resulting from the application of external stress with a counter template during corneal vitrification. Additionally, in some embodiments, unlike orthokeratology, the present invention is capable of slowing progressive myopia, progressive axial elongation, any combination thereof without the need for continuous treatment every night, because the present invention provides effects that last for years rather than less than one day as orthokeratology, without clinically significant side effects or complications (such as corneal infection and scarring on the visual axis). In some embodiments, corneal vitrification (including but not limited to photovitrification) can slow progressive myopia, progressive axial elongation, or any combination thereof, wherein one or both progression is slowed by at least 30% as compared to those wearing conventional glasses or monocular soft contact lenses.

In some embodiments, corneal vitrification (including, but not limited to, photovitrification) can provide vision improvement, including, but not limited to, providing functional, synchronized vision at a plurality of viewing distances, including, but not limited to, near distance (about 40cm), intermediate distance (about 60 to 100cm), and far distance (300cm or more), and can provide compensation, at least in part, for age-related focal dysfunction, wherein functional vision is 20/40 or better (equivalent to 0.3logMAR or less) in Snellen expression (in Snellen terms), and wherein depth of field includes a range of distances for which vision is functional. In some embodiments, vision improvement may be provided by improving the quality of vision (QoV), including but not limited to, QoV measurements of depth of field, contrast sensitivity, stereo acuity, modulus transfer function, point spread function, and Strehl ratio.

In some embodiments, corneal vitrification (including but not limited to photovitrification) provides vision improvement and overcomes central visual field defects caused by diseases, including but not limited to retinal diseases, such as age-related macular degeneration, by altering the optical aberrations of the cornea using magnification of the image on the retina, repositioning of the image on the retina, or any combination thereof; wherein the imaging magnification provides retinal imaging that overlaps the functional region of the retina, and wherein the imaging on the retina is repositioned to at least one preferred retinal location that overlaps the functional region of the retina.

In some embodiments, this may be produced by altering optical aberrations (including but not limited to defocus and spherical aberration) by causing repositioning of the image on the retina using corneal vitrification. The estimate of imaging magnification resulting from corneal vitrification for varying defocus can be calculated using the Emsley standard simplified 60-diopter (60D) eye (Emsley simplified eye) shown in fig. 17, which has a single diopter face (at the cornea) and a refractive power (at the cornea) that does not match the assumed eye refractive index n' ═ 1.3333; the refractive index of air is 1.00. For this simplified eye, the +60D power corresponds to a single refractive surface with a radius of curvature r of 5.55 mm. Focal point F₁And F₂At-16.67 mm and +22.22mm, respectively.

For an emmetropic eye with Uncorrected Distance Visual Acuity (UDVA) 20/20(0.0logMAR) and an Emsley simplified eye with a refractive power of +60D, imaging the retina of an object at infinity at F2 is about 5 μm/arc of the object orientation (the retinal image F)₂for an object two definition is ca.5 μm per minute of arc the object topics). Thus, the 1mm imaging size on retina X is approximately equal to 200 minutes of arc (200min arc). If r decreases or increases, corresponding to increased or decreased power, respectively (and thus myopia or hyperopia, respectively), the retinal image size X increases and can be estimated by the size of the geometric aberration-free defocus blur disc (free defocus disc) Φ:

Φ＝3.483ΔL D_mm(equation 3)

Where Φ is defocus blur disc [ unit: arc splitting ],

Δ L is defocus [ unit: diopter ] and

D_mmis the pupil diameter [ unit: mm is]。

The retinal imaging size X (in μm) is 5 Φ. Possible UDVA (decimal unit) is 25/X.

FIGS. 18A and 18B show the calculated for three pupil diameters D using equation 3_mmRetina imaging size X values (2, 3 and 4mm) and possibly UDVA (in S)nellen is a unit) values-all Δ L values are in the range of 1 to 5D. The possible UDVA should be considered as the upper limit of the actual UDVA value, since it represents an aberration-free (other than defocus) value and also belongs to full function within corneal imaging; some parts of the corneal imaging will be dysfunctional due to geographic atrophy or other factors.

In some embodiments, image repositioning on the retina can occur by altering optical aberrations (including but not limited to roll, tilt, and coma) through corneal vitrification. The situation of the imaging magnification (including defocus and changes in other optical aberrations such as spherical aberration which only affects the radial distribution of the imaging) is different, and changes in aberrations (such as flip, tilt and coma) which are repositioned for the imaging affect the angular distribution of the imaging, thereby repositioning its center (i.e. the average position of all points in the imaging).

In some embodiments, corneal vitrification (including but not limited to photovitrification) can be used to stabilize, augment, or any combination thereof at least one of: including but not limited to adhesions of apposed stromal tissue following healing of corneal wounds; adhesion of donor graft corneal stromal tissue or synthetic graft material to apposed recipient donor stromal tissue; or any combination thereof; wherein the blocking is increased by 10% or more.

In some embodiments, the inventive devices and methods described herein are configured to target maximum beneficial effects including, but not limited to, corneal vitrification including, but not limited to, corneal photovitrification, corneal acoustic vitrification, or any combination thereof; changes in corneal structure and properties (including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination thereof); maximally maintain the steady state activity of corneal stromal cells, and minimally convert corneal stromal cells into fibroblasts and myofibroblasts; the normal diameter of the collagen fibers is maintained to the maximum extent; or any combination thereof, and the inventive devices and methods described herein are configured to minimize deleterious side effects, including but not limited to damage to corneal structures, altered healing of corneal structures and properties, including but not limited to corneal elastic modulus, corneal optical aberrations, or any combination thereof. In some embodiments, methods and systems of corneal vitrification, including but not limited to photovitrification, are configured not to impede a wound healing response (response), but to initially reduce deleterious wound healing effects.

In some embodiments, the anterior corneal stroma is the predominant corneal structure that is targeted to produce the greatest beneficial effect. In some embodiments, detrimental effects are minimized, including but not limited to detrimental changes to the structure, function, and properties of the non-vitrified matrix and the vitrified volume.

Corneal stromal tissue vitrification according to the methods and systems of the present invention can include alterations to corneal stromal tissue in vivo, including, but not limited to:

a-changes in matrix nanostructures, microstructures, and macrostructures (including but not limited to fiber/substrate composites);

b-alterations in matrix fiber/substrate and cellular functions (including but not limited to metabolism, motility, and interactions including signaling at all scales);

changes in C-matrix properties (including but not limited to mechanical, optical, thermal, and transport properties on all scales);

d-or any combination thereof.

In some embodiments, a combination of a selected photon source wavelength and an ocular fixation device with a thermally conductive optical element can provide enhanced targeting and maximization of favorable corneal stromal changes, as well as enhanced minimization of thermal damage to corneal structures, hi some embodiments, a photon source wavelength in the range of 1.87 to 1.93 μm and an ocular fixation device with a thermally conductive optical element provide enhanced targeting and maximization of favorable corneal stromal changes, as well as enhanced minimization of thermal damage to corneal structures, wherein a photon source wavelength in the range of 1.87 to 1.93 μm utilizes the temperature (T) dependence of the corneal absorption coefficient α in that wavelength range, as shown in FIGS. 7 and 8, as T increases from 22 to 70 ℃, α for water (since water is the predominant chromophore,thus adding more than 30% to the cornea α), in some embodiments, this T dependence can be used to facilitate the process of light induced vitrification (PV) under Tx conditions that are matched except for the photon source wavelength, as shown in the example of FIG. 19. FIG. 19 shows two T profiles calculated using a numerical finite element axisymmetric transient conduction transfer model to obtain a two-dimensional (2-D) T profile along the radiation centerline (r 0. fig.. 19. the calculations are accomplished using (A) a volume of spatial nodes with non-uniform spacing in the 50 radial and 47 axial directions, (B) a circular cross-section with a diameter of 500 μm and 50W/cm2 with flat-topped radiation for 150ms of radiation, (C) a sapphire optical element (10mm diameter, 1mm thickness) in contact with the anterior corneal surface, and (D) a constant pressure heat capacity C.C._p3.2 joules/(g deg.C), thermal conductivity K2.9X 10^-3W/(cm deg.C), thermal diffusivity kappa 8.6X 10^-3 cm 2/s, (E) different water absorption coefficient at 1.93 μm, α ═ 125cm^-1At 1.90 μm, at 35 ℃ α ═ 114cm^-1And the doubling increased linearly to α ═ 142cm at 75 deg.C^-1As shown in fig. 8. In the absence of an ocular fixation device with a thermally conductive optical element in contact with the anterior corneal surface and providing a temperature within ± 5 degrees of the physiological corneal surface T (approximately 35 ℃) during the photovitrification process, both T distributions under 1.90 μm and 1.93 μm photo-irradiation have a maximum of T at the anterior corneal membrane and basal epithelium, reaching a much higher value of T than shown in fig. 19, thereby destroying the anterior corneal membrane and basal epithelium. The ocular fixation device with thermally conductive optical element eliminates part of the heat generated by the photo-irradiation, creating a maximum of T at the corneal stroma, as shown in fig. 19. In addition, the T-dependence of the corneal absorption coefficient also makes the effect of two photo-irradiations at different photon wavelengths different. The T-distributions of the PV Tx of 1.90 μm and 1.93 μm have the same peak T-value of about 75 ℃, but the T-distribution of 1.90 μm targets a larger volume of corneal stromal tissue over an extended temperature range (i.e., 50 to 75 ℃); in this case, 1.90 μm PV Tx produces a greater beneficial effect. A T profile of 1.90 μm also provides a greater degree of minimization of heat and thermal damage to the anterior basement membrane and the basal epithelium.

In some embodiments, corneal photovitrification can be optimized by the following time-dependent waveform changes, namely:

a single pulse of photo-irradiation, or

A plurality of photo-irradiation pulse sequences;

wherein the change in the time-dependent waveform may be:

at least one time-dependent waveform change of at least one pulse to change the instantaneous power during the pulse waveform,

a time-dependent interval of 10ms to 200ms between the plurality of pulses;

or any combination thereof.

In some embodiments, several photo-vitrification (PV) process (Tx) parameters can be used to target and maximize the beneficial effects and minimize the detrimental effects, wherein the PV Tx parameters include, but are not limited to: wavelength, single pulse waveform (i.e., irradiance versus time), multi-pulse waveform, Tx area, Tx geometry, reverse template applied external stress, or any combination thereof. In some embodiments, table 1 lists the range of PV Tx parameters that can be used to target and maximize the beneficial effects and minimize the detrimental effects: exemplary ranges of processing parameters according to at least some embodiments of the invention; it should be understood that the PV Tx parameter may vary with the intended usage indication, thus several ranges of the PV Tx parameter are specified.

Table 2 provides words and/or terms in the context of at least some embodiments of the present invention.

TABLE 1: exemplary ranges of processing parameters according to at least some embodiments of the present invention

TABLE 1 (continuation): exemplary ranges of processing parameters according to at least some embodiments of the present invention

TABLE 2: words and/or terms that are mentioned in at least some embodiments of the present invention.

Claims

1. A photo-vitrification system comprising:

a device for the vitrification of light-induced glass,

wherein the photovitrification device includes at least one photon source;

wherein the at least one photon source includes, but is not limited to:

at least one laser source;

at least one intense pulsed light source;

or any combination thereof;

wherein the photovitrification device is configured for in vivo corneal photovitrification;

wherein the in vivo corneal photovitrification results in at least 1% vitrification of at least one treated volume of corneal stromal tissue in vivo in an in vivo cornea of an in situ eye;

wherein the in vivo corneal photovitrification comprises heating the in vivo corneal stromal tissue of an in situ eye's in vivo cornea to a maximum temperature at a heating rate in a range of 5 ℃ per second to 20000 ℃ per second; continuing to heat the intrabody corneal stromal tissue of the in situ eye's intrabody cornea at the maximum temperature for a period of time to produce vitrified embedded stromal tissue within the treated volume, wherein the maximum temperature is between 50 ℃ and 100 °, and the period of time exceeds 0.02 seconds and is less than 2 seconds.

2. The photopolymerization system of claim 1, wherein said in vivo corneal photopolymerization produces a vitrified corneal stromal tissue formed within said in vivo corneal stromal tissue of the in vivo cornea of the in situ eye, said vitrified corneal stromal tissue having undergone a structural and property change from a naturally occurring tissue to a non-naturally occurring vitreous tissue.

3. The photovitrification system of claim 2 wherein the vitrified corneal stromal tissue of an in situ cornea of an in situ eye has elastic modulus properties different from the naturally occurring tissue, the differences in elastic modulus properties including but not limited to at least one of:

an increase in axial modulus of at least 10%, wherein the axial modulus passes through the cornea from anterior to posterior stroma,

an increase in shear modulus of at least 10%, and

combinations thereof.

4. The photovitrification system of claim 1, wherein the treated volume is at the maximum temperature T_maxTo a lower temperature T_maxCorneal stromal tissue within the heat affected zone treated in a temperature range of-5 ℃.

5. The photo-vitrification system of claim 1 further configured to improve vision by:

altering at least one of the optical aberrations of the cornea,

wherein the corneal optical aberrations include at least one of the following aberrations:

1) a low order aberration, wherein the low order aberration comprises at least one of flip, tilt, defocus, and astigmatism;

2) a higher order aberration; and

3) at least 51% of the aberrations cannot be described by Zernike polynomials up to and including the 8 th radial order.

6. The photovitrification system of claim 1 further configured to compensate for age-related focus dysfunction, wherein the compensation for age-related focus dysfunction provides at least one of:

1) functionally synchronizing vision at a plurality of distances, including near distance, intermediate distance, and far distance; and

2) increased depth of field;

wherein the functional vision is 20/40 in the Snellen expression pattern, corresponding to 0.3logMAR, and

wherein the short distance is 40cm, the medium distance is 60 to 100cm, and the long distance is at least 300 cm; and

wherein the depth of field comprises a range of distances for which vision is functional.

7. The photovitrification system of claim 1 further configured to slow a rate of at least one of:

progression of myopia

Progression of ocular axis elongation; and

any combination thereof;

wherein either or both progression is slowed by at least 30% as compared to those wearing conventional or monocular soft contact lenses.

8. The photovitrification system of claim 1 further configured to cause at least one of:

enlarging the image on the retina;

repositioning the imaging on the retina; and

any combination thereof;

wherein the on-retina imaging magnification provides retinal imaging of the functional region overlapping the macula, an

Wherein the on-retina imaging is repositioned to at least one preferred retina position overlapping a functional region of the macula lutea.

9. The photovitrification system of claim 1 further configured to cause at least one of:

enlarging the image on the retina;

repositioning the imaging on the retina; and

any combination thereof;

wherein the on-retina imaging magnification provides retinal imaging that overlaps a functional region of the retina, an

Wherein the on-retina imaging is repositioned to at least one preferred retinal location that overlaps a functional area of the retina.

10. The photovitrification system of claim 1 further configured to cause stabilization or reduction, or any combination thereof, of:

naturally occurring corneal ectasia;

iatrogenic corneal ectasia; or

Any combination thereof;

wherein the reduction in corneal ectasia comprises at least one local change in corneal curvature within at least one local area defined by r, theta coordinates, wherein the at least one local change in corneal curvature is between 0.10 diopters and 20 diopters.

11. The photovitrification system of claim 1 further configured to cause stabilization or augmentation of at least one of the following or any combination thereof:

adhesions of apposed stromal tissue, including but not limited to after corneal wound healing;

adhesion of donor graft corneal stromal tissue or synthetic implant material to apposed recipient donor stromal tissue;

or any combination thereof;

wherein the blocking is increased by 10% or more.

12. The photovitrification system of claim 1 wherein the at least one photon source is configured to generate at least one photon output having at least one wavelength at which an absorption coefficient of water at room temperature is between 20 and 300cm^-1Within the range of (a).

13. The photo-vitrification system of claim 1 wherein the at least one laser source is at least one of the following lasers:

i) a semiconductor diode laser;

ii) a solid state laser comprising a host material doped with at least one laser material.

14. The photovitrification system of claim 1 including the at least one photon source equipped with a wavelength selective and bandwidth narrowing optical element that provides a light output.

15. The photovitrification system of claim 1 further comprising:

i) time-dependent waveform modification of a single photo-irradiation pulse, or

ii) a time-dependent waveform change of a sequence of a plurality of photo-induced irradiation pulses;

wherein the time-dependent waveform change can be:

i) at least the time-dependent waveform of at least one pulse is varied, thereby varying the instantaneous power during the pulse waveform,

ii) a duration of 10 to 200 milliseconds between pulses;

or any combination thereof;

wherein each pulse has a pulse energy within a time window of 20 to 2000 milliseconds.

16. The photovitrification system of claim 1 further comprising a photon pulse sequence configured for stabilization prior to a photovitrification process, the stabilization including a lower temperature heating than a temperature initially used for treating corneal tissue.

17. The photovitrification system of claim 1 wherein the predetermined photon output energy is in a range of 20 to 1000mJ per pulse per treatment area, the treatment areaEach treatment zone is between 0.2 and 100mm based on full width half maximum intensity values for the shape of the zone bounded by the polar coordinates r, theta on the cornea in vivo²Within the range of (1).

18. The photovitrification system of claim 1 further comprising a fiber optic delivery system configured to create a corneal curvature gradient between and within at least one of the following locations:

an angle segment, a diameter segment, or any combination thereof;

wherein the corneal curvature gradient is in a range of 0.1 to 3 diopters per millimeter.

19. The photovitrification system of claim 1 further comprising an ocular fixation device with a thermally conductive optical element in contact with the anterior corneal surface and providing a temperature within ± 5 degrees of a physiological corneal surface T during a photovitrification process.

20. The photovitrification system of claim 1 including a means of providing an external stress to the corneal stromal tissue being treated during the treatment, the means of providing an external stress including the addition of a counter template positioned on a posterior surface of an optical element of the ocular fixation device in contact with an anterior surface of the cornea;

wherein the counter template comprises a projection in the range of 5 μm to 200 μm thickness protruding from the posterior surface of the optical element of the eye fixation device.

21. The photovitrification system of claim 20 wherein:

the treated volume of the in vivo corneal stromal tissue of the in situ cornea of the eye is densified by the external stress,

wherein the external stress applied to the anterior surface of the cornea is related to the pressure applied to at least one treated volume of the in vivo corneal stromal tissue of the in situ eye's in vivo cornea;

wherein the external stress is associated with at least a 5% increase in density of an in vivo corneal stromal tissue in at least one treated volume of the in vivo corneal vitrifying embedded stromal tissue of an in situ cornea of an eye.

22. The photovitrification system of claim 1 wherein the photon source is at least one intense pulsed light source and wherein the photovitrification system includes several components: at least one intense pulsed light source, at least one optical filter, an optical transmission subsystem, a photomask, and an eye fixation device.

23. The photo-vitrification system of claim 1 further configured to generate a plurality of semiconductor diode laser outputs oriented such that each semiconductor diode laser output is directly coupled into a single fiber of a fiber optic transmission subsystem,

wherein each of the plurality of semiconductor diode laser outputs is individually controlled in terms of at least one of the following output characteristics selected from the group consisting of: wavelength, output shape, time-dependent pulse distribution, pulse repetition frequency, and pulse energy.

24. The photovitrification system of claim 1 wherein the at least one laser source outputs collimated beams configured to be directional such that each beam is:

ii) split into two or more beams by an optical subsystem comprising at least one mirror, at least one beam splitter, at least one focusing lens, at least one dimmer, or any combination thereof, wherein each of the beamlets is coupled into a single fiber in the fiber optic transmission subsystem, or

iii) any combination thereof;

wherein each laser output is in the form of a beam and/or beamlet and is individually controlled in terms of at least one of the following output characteristics, selected from the group consisting of: wavelength, output shape, time-dependent pulse distribution, pulse repetition frequency, and pulse energy;

wherein the at least one dimmer is configured to adjust at least one characteristic of each laser output; and

wherein the at least one dimmer is selected from the group consisting of: iris, variable transmission filter, shutter, electro-optic and/or acousto-optic dimmer, or any combination thereof.

25. The photo-vitrification system of claim 5, wherein the higher order aberrations include spherical aberration, coma, trefoil, and higher order astigmatism.